Boron-containing small molecules as anti-protozoal agents

ABSTRACT

This invention provides, among other things, novel compounds useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a National Stage of filed International PatentApplication Serial No. PCT/US2009/060914 filed Oct. 15, 2009 andpublished as WO 2010/045503 A1, which claims the benefit of U.S.Provisional Pat. App. No. 61/105,759, filed Oct. 15, 2008, U.S.Provisional Pat. App. No. 61/105,763, filed Oct. 15, 2008, U.S.Provisional Pat. App. No. 61/110,907, filed Nov. 3, 2008, U.S.Provisional Pat. App. No. 61/119,956, filed Dec. 4, 2008, U.S.Provisional Pat. App. No. 61/148,241, filed Jan. 29, 2009, U.S.Provisional Pat. App. No. 61/162,321, filed Mar. 22, 2009 and U.S.Provisional Pat. App. No. 61/162,325, filed Mar. 22, 2009 each of whichis incorporated by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

The global rise of protozoa resistant to antimicrobials in general,poses a major threat. Deployment of massive quantities of antimicrobialagents into the ecosphere during the past 60 years has introduced apowerful selective pressure for the emergence and spread ofantimicrobial-resistant pathogens. Thus, there is a need to discover newbroad spectrum antimicrobials, such as antiprotozoals, useful incombating microorganisms, especially those with multidrug-resistance.

Boron-containing molecules, such as oxaboroles, useful as antimicrobialshave been described previously, such as in U.S. Pat. Pubs. US20060234981and US20070155699. Generally speaking, an oxaborole has the followingstructure and substituent numbering system:

It has now been discovered that certain classes of oxaboroles which aresurprisingly effective antiprotozoals. This, and other uses of theseoxaboroles are described herein.

SUMMARY OF THE INVENTION

This invention provides, among other things, novel compounds useful fortreating protozoa infections, pharmaceutical compositions containingsuch compounds, as well as combinations of these compounds with at leastone additional therapeutically effective agent.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 displays biological data for the compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Abbreviations

As used herein, the singular forms “a,” “an”, and “the” include pluralreferences unless the context clearly dictates otherwise. For example,reference to “an active agent” includes a single active agent as well astwo or more different active agents in combination. It is to beunderstood that present teaching is not limited to the specific dosageforms, carriers, or the like, disclosed herein and as such may vary.

The abbreviations used herein generally have their conventional meaningwithin the chemical and biological arts.

The following abbreviations have been used: aq. is aqueous; AcOH isacetic acid; ACTBr is cetyltrimethylammonium bromide;B₂pin₂-bis(pinacolato)diboron; Boc is tert-butoxy carbonyl;Boc₂O-di-tert-butyl dicarbonate; BzOOH-benzoyl peroxide; Cs₂CO₃ iscesium carbonate; DABCO is 1,4-diazabicyclo[2.2.2]octane; DCM isdichloromethane or methylene chloride; DIAD is diisopropylazodicarboxylate; DIEA is diisopropylethylamine;N,N-Diisopropylethylamine is DIPEA; DMAP is 4-(dimethylamino)pyridine;DME is 1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO isdimethylsulfoxide; eq. is equivalent; EtOAc is ethyl acetate; EtOH isethanol; Et₂O is diethyl ether;EDCI-N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride;m-CPBA-3-chloroperoxybenzoic acid; equiv-equivalent; h is hours; HATU isO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HCl is hydrochloric acid; HPLC is high pressureliquid chromatography; ISCO Companion is automated flash chromatographyequipment with fraction analysis by UV absorption available fromPresearch; KOAc is potassium acetate; K₂CO₃ is potassium carbonate;LiAlH₄ or LAH is lithium aluminum hydride; LDA is lithiumdiisopropylamide; LHMDS is lithium bis(trimethylsilyl) amide; KHMDS ispotassium bis(trimethylsilyl) amide; LiOH is lithium hydroxide; m-CPBAis 3-chloroperoxybenzoic acid; MeCN is acetonitrile; MeOH is methanol;MgSO₄ is magnesium sulfate; mins or min is minutes; Mp or MP is meltingpoint; NaCNBH₃ is sodium cyanoborohydride; NaOH is sodium hydroxide;Na₂SO₄ is sodium sulfate; NH₄Cl is ammonium chloride; N₂ is nitrogen;NMM-N-methylmorpholine; n-BuLi is n-butyllithium; overnight is O/N;PdCl₂(pddf) is 1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II); PrOH is 1-propanol; iPrOH is 2-propanol; POCl₃ isphosphorus chloride oxide; RT or rt is room temperature; TFA istrifluoroacetic acid; Tf₂O is trifluoromethanesulfonic anhydride; THF istetrahydrofuran; THP-tetrahydropyranyl; TMSI is trimethylsilyl iodide;H₂O is water; Ac—acetyl; PTSA—para-toluene sulfonic acid; Pyr.—Pyridine;Cbz—benzyloxycarbonyl; PMB—p-methoxybenzyl; DHP—dihydropyran;CSA—camphor sulfonic acid; CTAB—cetyltrimethylammonium bromide;sat.—saturated; Cy—cyclohexyl; Ph—phenyl; Ar—aryl.

“Compound of the invention,” as used herein refers to the compoundsdiscussed herein, salts (e.g. pharmaceutically acceptable salts),prodrugs, solvates and hydrates of these compounds.

“Combination of the invention,” as used herein refers to the compoundsand antiprotozoals discussed herein as well as acids, bases, salt forms(such as pharmaceutically acceptable salts), prodrugs, solvates andhydrates of these compounds and antiprotozoals.

“Boron containing compounds”, as used herein, refers to the compounds ofthe invention that contain boron as part of their chemical formula.

MIC, or minimum inhibitory concentration, is the point where thecompound stops more than 50% of cell growth, preferably 60% of cellgrowth, preferably 70% of cell growth, preferably 80% of cell growth,preferably 90% of cell growth, relative to an untreated control.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents, which would result from writing thestructure from right to left, e.g., —CH₂O— is intended to also recite—OCH₂—.

The term “poly” as used herein means at least 2. For example, apolyvalent metal ion is a metal ion having a valency of at least 2.

“Moiety” refers to a radical of a molecule that is attached to theremainder of the molecule.

The symbol

, whether utilized as a bond or displayed perpendicular to a bond,indicates the point at which the displayed moiety is attached to theremainder of the molecule.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). In some embodiments, the term “alkyl” means astraight or branched chain, or combinations thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals. Examples of saturated hydrocarbon radicals include, but arenot limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom. In someembodiments, the term “heteroalkyl,” by itself or in combination withanother term, means a stable straight or branched chain, or combinationsthereof, consisting of the stated number of carbon atoms and at leastone heteroatom. In an exemplary embodiment, the heteroatoms can beselected from the group consisting of B, O, N and S, and wherein thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) B, O, N andS may be placed at any interior position of the heteroalkyl group or atthe position at which the alkyl group is attached to the remainder ofthe molecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃. Similarly, the term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 to 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms. In an exemplary embodiment, theheteroatom is selected from B, N, O, and S, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, 6-quinolyl, dioxaborolane, dioxaborinane and dioxaborepane.Substituents for each of the above noted aryl and heteroaryl ringsystems are selected from the group of acceptable substituents describedbelow.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, -halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′,—NR′″″—C(NR′R″R′″)═NR″″, —NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR″SO₂R′, —CN, —NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to (2 m′+1), wherem′ is the total number of carbon atoms in such radical. R′, R″, R″′, R″″and R′″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., arylsubstituted with 1-3 halogens, substituted or unsubstituted alkyl,alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R″′, R″″ and R′″″groups when more than one of these groups is present. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR′″″—C(NR′R″R′″)═NR″″,—NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN,—NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in anumber ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R″′, R″″ and R′″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R″′,R″″ and R′″″ groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

“Ring” as used herein, means a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. A ringincludes fused ring moieties. The number of atoms in a ring is typicallydefined by the number of members in the ring. For example, a “5- to7-membered ring” means there are 5 to 7 atoms in the encirclingarrangement. Unless otherwise specified, the ring optionally includes aheteroatom. Thus, the term “5- to 7-membered ring” includes, for examplephenyl, pyridinyl and piperidinyl. The term “5- to 7-memberedheterocycloalkyl ring”, on the other hand, would include pyridinyl andpiperidinyl, but not phenyl. The term “ring” further includes a ringsystem comprising more than one “ring”, wherein each “ring” isindependently defined as above.

As used herein, the term “heteroatom” includes atoms other than carbon(C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur(S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B).

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include triflate, chloro, bromoand iodo groups; sulfonic ester groups, such as mesylate, tosylate,brosylate, nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl and substituted or unsubstitutedheterocycloalkyl groups.

By “effective” amount of a drug, formulation, or permeant is meant asufficient amount of an active agent to provide the desired local orsystemic effect. A “Topically effective,” “Cosmetically effective,”“pharmaceutically effective,” or “therapeutically effective” amountrefers to the amount of drug needed to effect the desired therapeuticresult.

“Topically effective” refers to a material that, when applied to theskin, nail, hair, claw or hoof produces a desired pharmacological resulteither locally at the place of application or systemically as a resultof transdermal passage of an active ingredient in the material.

“Cosmetically effective” refers to a material that, when applied to theskin, nail, hair, claw or hoof, produces a desired cosmetic resultlocally at the place of application of an active ingredient in thematerial.

The term “pharmaceutically acceptable salt” is meant to include a saltof a compound of the invention which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the inventioncontain relatively basic functionalities, acid addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., “Pharmaceutical Salts”, Journal ofPharmaceutical Science 66: 1-19 (1977)). Certain specific compounds ofthe invention contain both basic and acidic functionalities that allowthe compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompounds in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinreadily undergo chemical changes under physiological conditions toprovide the compounds of the invention. Additionally, prodrugs can beconverted to the compounds of the invention by chemical or biochemicalmethods in an ex vivo environment.

Certain compounds of the invention can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present invention. Certain compounds of the invention mayexist in multiple crystalline or amorphous forms.

Certain compounds of the invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention. The graphic representations of racemic,ambiscalemic and scalemic or enantiomerically pure compounds used hereinare taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and brokenwedges are used to denote the absolute configuration of a stereocenterunless otherwise noted. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms areincluded.

Compounds of the invention can exist in particular geometric orstereoisomeric forms. The invention contemplates all such compounds,including cis- and trans-isomers, (−)- and (+)-enantiomers, (R)- and(S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, such as enantiomericallyor diastereomerically enriched mixtures, as falling within the scope ofthe invention. Additional asymmetric carbon atoms can be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

Optically active (R)- and (S)-isomers and d and l isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If, for instance, a particular enantiomer of acompound of the present invention is desired, it can be prepared byasymmetric synthesis, or by derivatization with a chiral auxiliary,where the resulting diastereomeric mixture is separated and theauxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group,such as an amino group, or an acidic functional group, such as acarboxyl group, diastereomeric salts can be formed with an appropriateoptically active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means known in the art, and subsequent recovery of thepure enantiomers. In addition, separation of enantiomers anddiastereomers is frequently accomplished using chromatography employingchiral, stationary phases, optionally in combination with chemicalderivatization (e.g., formation of carbamates from amines).

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe invention, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable vehicle” refers to any formulation or carrier medium thatprovides the appropriate delivery of an effective amount of an activeagent as defined herein, does not interfere with the effectiveness ofthe biological activity of the active agent, and that is sufficientlynon-toxic to the host or patient. Representative carriers include water,oils, both vegetable and mineral, cream bases, lotion bases, ointmentbases and the like. These bases include suspending agents, thickeners,penetration enhancers, and the like. Their formulation is well known tothose in the art of cosmetics and topical pharmaceuticals. Additionalinformation concerning carriers can be found in Remington: The Scienceand Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins(2005) which is incorporated herein by reference.

“Pharmaceutically acceptable topical carrier” and equivalent terms referto pharmaceutically acceptable carriers, as described herein above,suitable for topical application. An inactive liquid or cream vehiclecapable of suspending or dissolving the active agent(s), and having theproperties of being nontoxic and non-inflammatory when applied to theskin, nail, hair, claw or hoof is an example of apharmaceutically-acceptable topical carrier. This term is specificallyintended to encompass carrier materials approved for use in topicalcosmetics as well.

The term “pharmaceutically acceptable additive” refers to preservatives,antioxidants, fragrances, emulsifiers, dyes and excipients known or usedin the field of drug formulation and that do not unduly interfere withthe effectiveness of the biological activity of the active agent, andthat is sufficiently non-toxic to the host or patient. Additives fortopical formulations are well-known in the art, and may be added to thetopical composition, as long as they are pharmaceutically acceptable andnot deleterious to the epithelial cells or their function. Further, theyshould not cause deterioration in the stability of the composition. Forexample, inert fillers, anti-irritants, tackifiers, excipients,fragrances, opacifiers, antioxidants, gelling agents, stabilizers,surfactant, emollients, coloring agents, preservatives, bufferingagents, other permeation enhancers, and other conventional components oftopical or transdermal delivery formulations as are known in the art.

The terms “enhancement,” “penetration enhancement” or “permeationenhancement” relate to an increase in the permeability of the skin,nail, hair, claw or hoof to a drug, so as to increase the rate at whichthe drug permeates through the skin, nail, hair, claw or hoof. Theenhanced permeation effected through the use of such enhancers can beobserved, for example, by measuring the rate of diffusion of the drugthrough animal skin, nail, hair, claw or hoof using a diffusion cellapparatus. A diffusion cell is described by Merritt et al. DiffusionApparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp.161-162. The term “permeation enhancer” or “penetration enhancer”intends an agent or a mixture of agents, which, alone or in combination,act to increase the permeability of the skin, nail, hair or hoof to adrug.

The term “excipients” is conventionally known to mean carriers, diluentsand/or vehicles used in formulating drug compositions effective for thedesired use.

The term “topical administration” refers to the application of apharmaceutical agent to the external surface of the skin, nail, hair,claw or hoof, such that the agent crosses the external surface of theskin, nail, hair, claw or hoof and enters the underlying tissues.Topical administration includes application of the composition to intactskin, nail, hair, claw or hoof, or to a broken, raw or open wound ofskin, nail, hair, claw or hoof. Topical administration of apharmaceutical agent can result in a limited distribution of the agentto the skin and surrounding tissues or, when the agent is removed fromthe treatment area by the bloodstream, can result in systemicdistribution of the agent.

The term “transdermal delivery” refers to the diffusion of an agentacross the barrier of the skin, nail, hair, claw or hoof resulting fromtopical administration or other application of a composition. Thestratum corneum acts as a barrier and few pharmaceutical agents are ableto penetrate intact skin. In contrast, the epidermis and dermis arepermeable to many solutes and absorption of drugs therefore occurs morereadily through skin, nail, hair, claw or hoof that is abraded orotherwise stripped of the stratum corneum to expose the epidermis.Transdermal delivery includes injection or other delivery through anyportion of the skin, nail, hair, claw or hoof or mucous membrane andabsorption or permeation through the remaining portion. Absorptionthrough intact skin, nail, hair, claw or hoof can be enhanced by placingthe active agent in an appropriate pharmaceutically acceptable vehiclebefore application to the skin, nail, hair, claw or hoof. Passivetopical administration may consist of applying the active agent directlyto the treatment site in combination with emollients or penetrationenhancers. As used herein, transdermal delivery is intended to includedelivery by permeation through or past the integument, i.e. skin, nail,hair, claw or hoof.

The terms “effective amount” or a “therapeutically effective amount” ofa drug or pharmacologically active agent refers to a nontoxic butsufficient amount of the drug or agent to provide the desired effect. Inthe oral dosage forms of the present disclosure, an “effective amount”of one active of the combination is the amount of that active that iseffective to provide the desired effect when used in combination withthe other active of the combination. The amount that is “effective” willvary from subject to subject, depending on the age and general conditionof the individual, the particular active agent or agents, and theappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

The phrases “active ingredient”, “therapeutic agent”, “active”, or“active agent” mean a chemical entity which can be effective in treatinga targeted disorder, disease or condition.

The phrase “pharmaceutically acceptable” means moieties or compoundsthat are, within the scope of medical judgment, suitable for use inhumans without causing undesirable biological effects such as unduetoxicity, irritation, allergic response, and the like, for example.

The phrase “oral dosage form” means any pharmaceutical compositionadministered to a subject via the oral cavity. Exemplary oral dosageforms include tablets, capsules, films, powders, sachets, granules,solutions, solids, suspensions or as more than one distinct unit (e.g.,granules, tablets, and/or capsules containing different actives)packaged together for co-administration, and other formulations known inthe art. An oral dosage form can be one, two, three, four, five or sixunits. When the oral dosage form has multiple units, all of the unitsare contained within a single package, (e.g. a bottle or other form ofpackaging such as a blister pack). When the oral dosage form is a singleunit, it may or may not be in a single package. In a preferredembodiment, the oral dosage form is one, two or three units. In aparticularly preferred embodiment, the oral dosage form is one unit.

The phrase “unit”, as used herein, refers to the number of discreteobjects to be administered which comprise the dosage form. In someembodiments, the dosage form includes a compound of the invention in onecapsule. This is a single unit. In some embodiments, the dosage formincludes a compound of the invention as part of a therapeuticallyeffective dosage of a cream or ointment. This is also a single unit. Insome embodiments, the dosage form includes a compound of the inventionand another active ingredient contained within one capsule, or as partof a therapeutically effective dosage of a cream or ointment. This is asingle unit, whether or not the interior of the capsule includesmultiple discrete granules of the active ingredient. In someembodiments, the dosage form includes a compound of the invention in onecapsule, and the active ingredient in a second capsule. This is a twounit dosage form, such as two capsules or tablets, and so such units arecontained in a single package. Thus the term ‘unit’ refers to the objectwhich is administered to the animal, not to the interior components ofthe object.

The term, “prodrug”, as defined herein, is a derivative of a parent drugmolecule that exerts its pharmacological effect only after chemicaland/or enzymatic conversion to its active form in vivo. Prodrugs includethose designed to circumvent problems associated with delivery of theparent drug. This may be due to poor physicochemical properties, such aspoor chemical stability or low aqueous solubility, and may also be dueto poor pharmacokinetic properties, such as poor bioavailability or poorhalf-life. Thus, certain advantages of prodrugs may include improvedchemical stability, absorption, and/or PK properties of the parentcarboxylic acids. Prodrugs may also be used to make drugs more “patientfriendly,” by minimizing the frequency (e.g., once daily) or route ofdosing (e.g., oral), or to improve the taste or odor if given orally, orto minimize pain if given parenterally.

In some embodiments, the prodrugs are chemically more stable than theactive drug, thereby improving formulation and delivery of the parentdrug, compared to the drug alone.

Prodrugs for carboxylic acid analogs of the invention may include avariety of esters. In an exemplary embodiment, the pharmaceuticalcompositions of the invention include a carboxylic acid ester. In anexemplary embodiment, the prodrug is suitable for treatment/preventionof those diseases and conditions that require the drug molecule to crossthe blood brain barrier. In an exemplary embodiment, the prodrug entersthe brain, where it is converted into the active form of the drugmolecule. In one embodiment, a prodrug is used to enable an active drugmolecule to reach the inside of the eye after topical application of theprodrug to the eye. Additionally, a prodrug can be converted to itsparent compound by chemical or biochemical methods in an ex vivoenvironment. For example, a prodrug can be slowly converted to itsparent compound when placed in a transdermal patch reservoir with asuitable enzyme or chemical reagent.

“Antibiotic”, as used herein, is a compound which can kill or inhibitthe growth of bacteria. The term antibiotic is broad enough to encompassacids, bases, salt forms (such as pharmaceutically acceptable salts),prodrugs, solvates and hydrates of the antibiotic compound.

“Antiprotozoal” or “antiprotozoa”, as used herein, is a compound whichcan kill or inhibit the growth of protozoa. The term antiprotozoal orantiprotozoa is broad enough to encompass acids, bases, salt forms (suchas pharmaceutically acceptable salts), prodrugs, solvates and hydratesof the antiprotozoal or antiprotozoa compound.

The term “microbial infection” or “infection by a microorganism” refersto any infection of a host by an infectious agent including, but notlimited to, viruses, bacteria, mycobacteria, fungus and parasites (see,e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson etal., eds., 12th ed. 1991); Williams et al., J. of Medicinal Chem.42:1481-1485 (1999), herein each incorporated by reference in theirentirety).

“Biological medium,” as used herein refers to both in vitro and in vivobiological milieus. Exemplary in vitro “biological media” include, butare not limited to, cell culture, tissue culture, homogenates, plasmaand blood. In vivo applications are generally performed in mammals,preferably humans.

“Inhibiting” and “blocking,” are used interchangeably herein to refer tothe partial or full blockade of an enzyme, such as a beta-lactamase or aleucyl t-RNA synthetase.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include triflate, chloro, bromoand iodo groups; sulfonic ester groups, such as mesylate, tosylate,brosylate, nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “amino-protecting group” means a protecting group suitable forpreventing undesired reactions at an amino nitrogen. Representativeamino-protecting groups include, but are not limited to, formyl; acylgroups, for example alkanoyl groups, such as acetyl, trichloroacetyl ortrifluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl(Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl(Bn), trityl (Tr), and 1,1-di-(4′-methoxyphenyl)methyl; silyl groups,such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and thelike.

The term “hydroxy-protecting group” means a protecting group suitablefor preventing undesired reactions at a hydroxy group. Representativehydroxy-protecting groups include, but are not limited to, alkyl groups,such as methyl, ethyl, and tert-butyl; acyl groups, for example alkanoylgroups, such as acetyl; arylmethyl groups, such as benzyl (Bn),p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl(benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) andtert-butyldimethylsilyl (TBS); and the like.

Boron is able to form dative bonds (or coordination bonds) with oxygen,sulfur or nitrogen under some circumstances in this invention. Dativebonds are usually weaker than covalent bonds. In situations where aboron atom is covalently bonded to at least one oxygen, sulfur ornitrogen, and is at the same time datively bonded to an oxygen, sulfuror nitrogen, respectively, the dative bond and covalent bond between theboron and the two identical heteroatoms can interconvert or be in theform of a resonance hybrid. There is potential uncertainty surroundingthe exact nature and extent of electron sharing in these situations. Thestructures supplied are not intended to include any and all possiblebonding scenarios between boron and the atom to which it is bound. Nonlimiting examples of these bonds are as follows:

The compounds comprising a boron bonded to a carbon and threeheteroatoms (such as three oxygens described in this section) canoptionally contain a fully negatively charged boron or partiallynegatively charged boron, due to the nature of the dative bond betweenthe boron and one of the oxygens. Due to the negative charge, apositively charged counterion may associate with this compound, thusforming a salt. Examples of positively charged counterions include H⁺,H₃O⁺, calcium, sodium, ammonium, potassium. The salts of these compoundsare implicitly contained in descriptions of these compounds.

The present invention also encompasses compounds that are poly- ormulti-valent species, including, for example, species such as dimers,trimers, tetramers and higher homologs of the compounds of use in theinvention or reactive analogues thereof. For example, dimers can formunder the following conditions:

The present invention also encompasses compounds that are anhydrides ofthe cyclic boronic esters are synthesized by subjecting these compoundsto dehydrating conditions. Examples of these anhydrides are providedbelow:

Trimers of the compounds of the invention are also produced. Forexample, trimers of acyclic boronic esters can be formed as follows:

Polymers of the compounds of the invention are also produced through theremoval of certain protecting groups in strong acid. For example,trimers can be formed as follows:

Also of use in the present invention are compounds that are poly- ormulti-valent species, including, for example, species such as dimers,trimers, tetramers and higher homologs of the compounds of use in theinvention or reactive analogues thereof. The poly- and multi-valentspecies can be assembled from a single species or more than one speciesof the invention. For example, a dimeric construct can be “homo-dimeric”or “heterodimeric.” Moreover, poly- and multi-valent constructs in whicha compound of the invention or a reactive analogue thereof, is attachedto an oligomeric or polymeric framework (e.g., polylysine, dextran,hydroxyethyl starch and the like) are within the scope of the presentinvention. The framework is preferably polyfunctional (i.e. having anarray of reactive sites for attaching compounds of use in theinvention). Moreover, the framework can be derivatized with a singlespecies of the invention or more than one species of the invention.

Moreover, the present invention includes the use of compounds within themotif set forth in the formulae contained herein, which arefunctionalized to afford compounds having water-solubility that isenhanced relative to analogous compounds that are not similarlyfunctionalized. Thus, any of the substituents set forth herein can bereplaced with analogous radicals that have enhanced water solubility.For example, it is within the scope of the invention to replace ahydroxyl group with a diol, or an amine with a quaternary amine, hydroxyamine or similar more water-soluble moiety. In a preferred embodiment,additional water solubility is imparted by substitution at a site notessential for the activity towards the editing domain of the compoundsset forth herein with a moiety that enhances the water solubility of theparent compounds. Methods of enhancing the water-solubility of organiccompounds are known in the art. Such methods include, but are notlimited to, functionalizing an organic nucleus with a permanentlycharged moiety, e.g., quaternary ammonium, or a group that is charged ata physiologically relevant pH, e.g. carboxylic acid, amine. Othermethods include, appending to the organic nucleus hydroxyl- oramine-containing groups, e.g. alcohols, polyols, polyethers, and thelike. Representative examples include, but are not limited to,polylysine, polyethyleneimine, poly(ethyleneglycol) andpoly(propyleneglycol). Suitable functionalization chemistries andstrategies for these compounds are known in the art. See, for example,Dunn, R. L., et al., Eds. POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS, ACSSymposium Series Vol. 469, American Chemical Society, Washington, D.C.1991.

II. Introduction

The present invention provides novel boron compounds. The novelcompounds, as well as pharmaceutical compositions containing suchcompounds or combinations of these compounds with at least oneadditional therapeutically effective agent, can be used for, among otherthings, treating protozoal infections.

III. The Compounds

III. a) Cyclic Boronic Esters

In one aspect, the invention provides a compound of the invention. In anexemplary embodiment, the invention is a compound described herein. Inan exemplary embodiment, the invention is a compound according to aformula described herein.

In an exemplary embodiment, the compound of the invention has thefollowing structure:

wherein X is selected from the group consisting of substituted phenyl,substituted or unsubstituted phenylalkyl, substituted or unsubstitutedheteroaryl and unsubstituted cycloalkyl, R^(c) is H or unsubstitutedalkyl and R* is H or a negative charge, or a salt thereof. In anexemplary embodiment, R^(c) is H. In an exemplary embodiment, R^(c) ismethyl. In an exemplary embodiment, R^(c) is ethyl. In an exemplaryembodiment, R^(c) is unsubstituted C₃ alkyl. In an exemplary embodiment,X is substituted phenyl. In an exemplary embodiment, X is substitutedphenyl which is not monosubstituted with unsubstituted alkyl. In anexemplary embodiment, X is substituted phenyl which is notmonosubstituted with halosubstituted alkyl. In an exemplary embodiment,X is phenyl, substituted with at least one member selected from thegroup consisting of: halogen, cyano, nitro, OR, SR, NRR, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl, wherein each R is independently selected fromthe group consisting of substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. In anexemplary embodiment, X is phenyl, substituted with at least one or moreof the substituents described herein. In an exemplary embodiment, X isheteroaryl, optionally substituted with at least one or more of thesubstituents described herein: In an exemplary embodiment, X is phenyl,substituted with at least one member selected from the group consistingof halogen, cyano, nitro, OR, SR, NRR, unsubstituted alkyl,halosubstituted alkyl, unsubstituted alkoxy, alkyl substituted amidyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl, wherein each R is independently selected fromthe group consisting of substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. In anexemplary embodiment, X is not a phenyl which is monosubstituted withunsubstituted alkyl. In an exemplary embodiment, X is not a phenyl whichis monosubstituted with halosubstituted alkyl. In an exemplaryembodiment, X is not a phenyl which is only substituted with halogens.

In an exemplary embodiment, the compound of the invention has thefollowing structure:

wherein Y is selected from the group consisting of halogen,halo-substituted C₁-C₆ alkyl and unsubstituted C₁-C₆ alkyl; and R* isselected from the group consisting of H, a negative charge and apositively charged counterion, or a salt thereof. In an exemplaryembodiment, Y is an unsubstituted C₃ alkyl. In an exemplary embodiment,Y is an unsubstituted C₄ alkyl. In an exemplary embodiment, Y is anunsubstituted C₅ alkyl. In an exemplary embodiment, Y is anunsubstituted C₆ alkyl. In an exemplary embodiment, Y is selected fromthe group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl.In an exemplary embodiment, Y is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In an exemplaryembodiment, Y is halo-substituted C₁-C₆ alkyl. In an exemplaryembodiment, Y is C₁-C₆ alkyl, substituted with one halogen. In anexemplary embodiment, Y is C₁-C₆ alkyl, substituted with two halogens.In an exemplary embodiment, Y is C₁-C₆ alkyl, substituted with threehalogens. In an exemplary embodiment, Y is C₁-C₆ alkyl, substituted withfour halogens. In an exemplary embodiment, Y is C₁-C₆ alkyl, substitutedwith one fluorine. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with two fluorines. In an exemplary embodiment, Y is C₁-C₆alkyl, substituted with three fluorines. In an exemplary embodiment, Yis C₁-C₆ alkyl, substituted with four fluorines. In an exemplaryembodiment, Y is C₁-C₆ alkyl, substituted with one chlorine. In anexemplary embodiment, Y is C₁-C₆ alkyl, substituted with two chlorines.In an exemplary embodiment, Y is C₁-C₆ alkyl, substituted with threechlorines. In an exemplary embodiment, Y is C₁-C₆ alkyl, substitutedwith four chlorines. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with a combination of two different halogens. In anexemplary embodiment, Y is C₁-C₆ alkyl, substituted with at least onefluorine and at least one chlorine. In an exemplary embodiment, Y isC₁-C₆ alkyl, substituted with at least one fluorine and at least onebromine. In an exemplary embodiment, Y is C₁-C₆ alkyl, substituted withat least one chlorine and at least one bromine. In an exemplaryembodiment, Y is fluoro-substituted C₁-C₆ alkyl. In an exemplaryembodiment, Y is trifluoro-substituted C₁-C₆ alkyl. In an exemplaryembodiment, the compound of the invention has a structure which isselected from the group consisting of:

wherein R* is selected from the group consisting of H, a negative chargeand a positively charged counterion, or a salt thereof. In anotherexemplary embodiment, R* is H.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

In an exemplary embodiment, the compound has the following structure:

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

wherein Y¹ is a halogen, R* is H or a negative charge. In anotherexemplary embodiment, R* is H. In an exemplary embodiment, the compoundis H4 or H5 or H6 or H7 or H8 or H9 or H10, or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

wherein Y² is unsubstituted alkyl, R* is H or a negative charge. Inanother exemplary embodiment, R* is H. In an exemplary embodiment, Y² isunsubstituted C₁ alkyl. In an exemplary embodiment, Y² is unsubstitutedC₂ alkyl. In an exemplary embodiment, Y² is unsubstituted C₃ alkyl. Inan exemplary embodiment, Y² is unsubstituted n-propyl or isopropyl. Inan exemplary embodiment, Y² is unsubstituted C₄ alkyl. In an exemplaryembodiment, Y² is n-butyl or sec-butyl or iso-butyl or tert-butyl. In anexemplary embodiment, Y² is unsubstituted C₅ alkyl. In an exemplaryembodiment, Y² is unsubstituted C₆ alkyl. In an exemplary embodiment,the compound is H28 or H29 or H30 or H31 or H32 or H33, or a saltthereof.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

wherein Y³ is unsubstituted alkoxy, R* is H or a negative charge. Inanother exemplary embodiment, R* is H. In an exemplary embodiment, Y³ isunsubstituted C₁ alkoxy. In an exemplary embodiment, Y³ is unsubstitutedC₂ alkoxy. In an exemplary embodiment, Y³ is unsubstituted C₃ alkoxy. Inan exemplary embodiment, Y³ is n-propoxy. In an exemplary embodiment, Y³is isopropoxy. In an exemplary embodiment, Y³ is unsubstituted C₄alkoxy. In an exemplary embodiment, Y³ is unsubstituted C₅ alkoxy. In anexemplary embodiment, Y³ is unsubstituted C₆ alkoxy. In an exemplaryembodiment, the compound is H35 or H36 or H37 or H31 or H32 or H33, or asalt thereof.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

wherein Y⁵ is halosubstituted alkoxy, R* is H or a negative charge. Inanother exemplary embodiment, R* is H. In an exemplary embodiment, Y⁵ ishalosubstituted C₁ alkoxy. In an exemplary embodiment, Y⁵ ishalosubstituted C₂ alkoxy. In an exemplary embodiment, Y⁵ ishalosubstituted C₃ alkoxy. In an exemplary embodiment, Y⁵ ishalosubstituted C₄ alkoxy. In an exemplary embodiment, Y⁵ ishalosubstituted C₅ alkoxy. In an exemplary embodiment, Y⁵ ishalosubstituted C₆ alkoxy. In an exemplary embodiment, Y⁵ isfluoro-substituted C₁-C₆ alkoxy. In an exemplary embodiment, Y⁵ issubstituted with one or two or three halogens. In an exemplaryembodiment, Y⁵ is trifluoro-substituted C₁-C₆ alkoxy. In an exemplaryembodiment, Y⁵ is trifluoromethoxy.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

wherein Y⁶ is halosubstituted alkylthio, R* is H or a negative charge.In another exemplary embodiment, R* is H. In an exemplary embodiment, Y⁶is halosubstituted C₁ alkylthio. In an exemplary embodiment, Y⁶ ishalosubstituted C₂ alkylthio. In an exemplary embodiment, Y⁶ ishalosubstituted C₃ alkylthio. In an exemplary embodiment, Y⁶ ishalosubstituted C₄ alkylthio. In an exemplary embodiment, Y⁶ ishalosubstituted C₅ alkylthio. In an exemplary embodiment, Y⁶ ishalosubstituted C₆ alkylthio. In an exemplary embodiment, Y⁶ isfluoro-substituted C₁-C₆ alkylthio. In an exemplary embodiment, Y⁶ issubstituted with one or two or three halogens. In an exemplaryembodiment, Y⁶ is trifluoro-substituted C₁-C₆ alkylthio. In an exemplaryembodiment, Y⁵ is trifluoromethylthio.

In an exemplary embodiment, the compound of the invention is selectedfrom the group consisting of:

In an exemplary embodiment, the compound of the invention is:

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein R⁷ is unsubstituted alkyl and R⁸ is unsubstituted alkyl and R*is as described herein, or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

wherein Y⁴ is —NHC(O)R⁴, wherein R⁴ is unsubstituted alkyl, R* is H or anegative charge. In another exemplary embodiment, R* is H. In anexemplary embodiment, R⁴ is unsubstituted C₁ alkyl. In an exemplaryembodiment, R⁴ is unsubstituted C₂ alkyl. In an exemplary embodiment, R⁴is unsubstituted C₃ alkyl. In an exemplary embodiment, R⁴ isunsubstituted C₄ alkyl. In an exemplary embodiment, R⁴ is unsubstitutedC₅ alkyl. In an exemplary embodiment, R⁴ is unsubstituted C₆ alkyl. Inan exemplary embodiment, the compound of the invention is H51, or a saltthereof.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

wherein Y⁸ is —S(O)₂NHCHNR⁷R⁸, wherein R⁷ is unsubstituted alkyl, R⁸ isunsubstituted alkyl, R* is H or a negative charge. In another exemplaryembodiment, R* is H. In an exemplary embodiment, R⁷ is unsubstituted C₁alkyl and R⁸ is unsubstituted alkyl. In an exemplary embodiment, R⁷ isunsubstituted C₂ alkyl and R⁸ is unsubstituted alkyl. In an exemplaryembodiment, R⁷ is unsubstituted C₃ alkyl and R⁸ is unsubstituted alkyl.In an exemplary embodiment, R⁷ is unsubstituted C₄ alkyl and R⁸ isunsubstituted alkyl. In an exemplary embodiment, R⁷ is unsubstituted C₅alkyl and R⁸ is unsubstituted alkyl. In an exemplary embodiment, R⁷ isunsubstituted C₆ alkyl and R⁸ is unsubstituted alkyl. In an exemplaryembodiment, Y⁸ is —S(O)₂NHCHN(CH₃)₂.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein R* is H or a negative charge, R^(c) is as described herein andR², R³, R⁴, R⁵ and R⁶ are according to the entries in the followingtable, or a salt thereof

R² R³ R⁴ R⁵ R⁶ 1 F H H H H 2 H F H H H 3 H H F H H 4 H H H F H 5 H H H HF 6 Cl H H H H 7 H Cl H H H 8 H H Cl H H 9 H H H Cl H 10 H H H H Cl 11Br H H H H 12 H Br H H H 13 H H Br H H 14 H H H Br H 15 H H H H Br 16 IH H H H 17 H I H H H 18 H H I H H 19 H H H I H 20 H H H H I 21 CN H H HH 22 H CN H H H 23 H H CN H H 24 H H H CN H 25 H H H H CN 26 NO₂ H H H H27 H NO₂ H H H 28 H H NO₂ H H 29 H H H NO₂ H 30 H H H H NO₂ 31 Ph H H HH 32 H Ph H H H 33 H H Ph H H 34 H H H Ph H 35 H H H H Ph 36 —CH3 H H HH 37 H —CH3 H H H 38 H H —CH3 H H 39 H H H —CH3 H 40 H H H H —CH3 41—CH₂CH₃ H H H H 42 H —CH₂CH₃ H H H 43 H H —CH₂CH₃ H H 44 H H H —CH₂CH₃ H45 H H H H —CH₂CH₃ 46 —CF₃ H H H H 47 H —CF₃ H H H 48 H H —CF₃ H H 49 HH H —CF₃ H 50 H H H H —CF₃ 51 —OCH₃ H H H H 52 H —OCH₃ H H H 53 H H—OCH₃ H H 54 H H H —OCH₃ H 55 H H H H —OCH₃ 56 —OCH₂CH₃ H H H H 57 H—OCH₂CH₃ H H H 58 H H —OCH₂CH₃ H H 59 H H H —OCH₂CH₃ H 60 H H H H—OCH₂CH₃ 61 —OCH(CH₃)₂ H H H H 62 H —OCH(CH₃)₂ H H H 63 H H —OCH(CH₃)₂ HH 64 H H H —OCH(CH₃)₂ H 65 H H H H —OCH(CH₃)₂ 66 —NR⁷R⁸ H H H H 67 H—NR⁷R⁸ H H H 68 H H —NR⁷R⁸ H H 69 H H H —NR⁷R⁸ H 70 H H H H —NR⁷R⁸ 71—NH₂ H H H H 72 H —NH₂ H H H 73 H H —NH₂ H H 74 H H H —NH₂ H 75 H H H H—NH₂ 76 —N(CH₃)R⁸ H H H H 77 H —N(CH₃)R⁸ H H H 78 H H —N(CH₃)R⁸ H H 79 HH H —N(CH₃)R⁸ H 80 H H H H —N(CH₃)R⁸ 81 —N(CH₃)₂ H H H H 82 H —N(CH₃)₂ HH H 83 H H —N(CH₃)₂ H H 84 H H H —N(CH₃)₂ H 85 H H H H —N(CH₃)₂ 86—NHC(O)CH₃ H H H H 87 H —NHC(O)CH₃ H H H 88 H H —NHC(O)CH₃ H H 89 H H H—NHC(O)CH₃ H 90 H H H H —NHC(O)CH₃In an exemplary embodiment, for any of the entries in the above table,R^(c) is H. In an exemplary embodiment, for any of the entries in theabove table, R^(c) is methyl. In an exemplary embodiment, for any of theentries in the above table, R^(c) is ethyl. In an exemplary embodiment,for any of the entries in the above table, R^(c) is propyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is H or a negative charge, R^(d) is C₁-C₆ unsubstitutedalkylene and R², R³, R⁴, R⁵ and R⁶ are according to the entries in thefollowing table, or a salt thereof

R² R³ R⁴ R⁵ R⁶ 91 H H H H H 92 F H H H H 93 H F H H H 94 H H F H H 95 HH H F H 96 H H H H F 97 Cl H H H H 98 H Cl H H H 99 H H Cl H H 100 H H HCl H 101 H H H H Cl 102 Br H H H H 103 H Br H H H 104 H H Br H H 105 H HH Br H 106 H H H H Br 107 I H H H H 108 H I H H H 109 H H I H H 110 H HH I H 111 H H H H I 112 CN H H H H 113 H CN H H H 114 H H CN H H 115 H HH CN H 116 H H H H CN 117 NO₂ H H H H 118 H NO₂ H H H 119 H H NO₂ H H120 H H H NO₂ H 121 H H H H NO₂ 122 Ph H H H H 123 H Ph H H H 124 H H PhH H 125 H H H Ph H 126 H H H H Ph 127 —CH₃ H H H H 128 H —CH₃ H H H 129H H —CH₃ H H 130 H H H —CH₃ H 131 H H H H —CH₃ 132 —CH₂CH₃ H H H H 133 H—CH₂CH₃ H H H 134 H H —CH₂CH₃ H H 135 H H H —CH₂CH₃ H 136 H H H H—CH₂CH₃ 137 —CF₃ H H H H 138 H —CF₃ H H H 139 H H —CF₃ H H 140 H H H—CF₃ H 141 H H H H —CF₃ 142 —OCH₃ H H H H 143 H —OCH₃ H H H 144 H H—OCH₃ H H 145 H H H —OCH₃ H 146 H H H H —OCH₃ 147 —OCH₂CH₃ H H H H 148 H—OCH₂CH₃ H H H 149 H H —OCH₂CH₃ H H 150 H H H —OCH₂CH₃ H 151 H H H H—OCH₂CH₃ 152 —OCH(CH₃)₂ H H H H 153 H —OCH(CH₃)₂ H H H 154 H H—OCH(CH₃)₂ H H 155 H H H —OCH(CH₃)₂ H 156 H H H H —OCH(CH₃)₂ 157 —NR⁷R⁸H H H H 158 H —NR⁷R⁸ H H H 159 H H —NR⁷R⁸ H H 160 H H H —NR⁷R⁸ H 161 H HH H —NR⁷R⁸ 162 —NH₂ H H H H 163 H —NH₂ H H H 164 H H —NH₂ H H 165 H H H—NH₂ H 166 H H H H —NH₂ 167 —N(CH₃)R⁸ H H H H 168 H —N(CH₃)R⁸ H H H 169H H —N(CH₃)R⁸ H H 170 H H H —N(CH₃)R⁸ H 171 H H H H —N(CH₃)R⁸ 172—N(CH₃)₂ H H H H 173 H —N(CH₃)₂ H H H 174 H H —N(CH₃)₂ H H 175 H H H—N(CH₃)₂ H 176 H H H H —N(CH₃)₂ 177 —NHC(O)CH₃ H H H H 178 H —NHC(O)CH₃H H H 179 H H —NHC(O)CH₃ H H 180 H H H —NHC(O)CH₃ H 181 H H H H—NHC(O)CH₃In an exemplary embodiment, for any of the entries in the above table,R^(d) is methylene. In an exemplary embodiment, for any of the entriesin the above table, R^(d) is ethylene. In an exemplary embodiment, forany of the entries in the above table, R^(d) is propylene. In anexemplary embodiment, for any of the entries in the above table, R^(d)is ethyl substituted methylene.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of:

or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z⁵ is unsubstituted pyrimidinyl or unsubstituted pyrazinyl orunsubstituted pyridazinyl. In an exemplary embodiment, the compound ofthe invention has a structure which is selected from the groupconsisting of:

or a salt thereof. In an exemplary embodiment, the compound is H75 or asalt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z⁶ is halosubstituted pyridazinyl. In an exemplary embodiment,Z⁶ is pyridazinyl, substituted with one halogen. In an exemplaryembodiment, Z⁶ is pyridazinyl, substituted with two halogens. In anexemplary embodiment, Z⁶ is pyridazinyl, substituted with two chlorines.In an exemplary embodiment, the compound of the invention has astructure which is:

wherein each R¹⁴ is chlorine or fluorine, or a salt thereof. In anexemplary embodiment, each R¹⁴ is chlorine. In an exemplary embodiment,the compound is H76 or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein each R¹³ is independently selected from the group selected fromH, —SH and —OH. In an exemplary embodiment, each R¹³ is —SH or —OH. Inan exemplary embodiment, the compound is H77 or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z is thiophenyl. In an exemplary embodiment, the compound of theinvention has a structure which is:

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z¹ is unsubstituted alkylthiophenyl. In an exemplary embodiment,the compound of the invention has a structure which is

wherein Y⁷ is unsubstituted alkyl, R* is H or a negative charge. Inanother exemplary embodiment, R* is H. In an exemplary embodiment, Y⁷ isunsubstituted C₁ alkyl. In an exemplary embodiment, Y⁷ is unsubstitutedC₂ alkyl. In an exemplary embodiment, Y⁷ is unsubstituted C₃ alkyl. Inan exemplary embodiment, Y⁷ is unsubstituted C₄ alkyl. In an exemplaryembodiment, Y⁷ is unsubstituted C₅ alkyl. In an exemplary embodiment, Y⁷is unsubstituted C₆ alkyl.

In an exemplary embodiment, the compound is H64 or H65 or a saltthereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z² is unsubstituted benzothiophenyl. In an exemplary embodiment,the compound of the invention is H66 or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z² is halosubstituted benzothiophenyl. In an exemplaryembodiment, Z² is benzothiophenyl substituted with chloro. In anexemplary embodiment, Z² is benzothiophenyl substituted with fluoro. Inan exemplary embodiment, Z² is benzothiophenyl substituted with onehalogen. In an exemplary embodiment, Z² is benzothiophenyl substitutedwith two halogens. In an exemplary embodiment, Z² is benzothiophenylsubstituted with two fluorines. In an exemplary embodiment, Z² isbenzothiophenyl substituted with two chlorines. In an exemplaryembodiment, Z² is benzothiophenyl substituted with a fluorine and achlorine. In an exemplary embodiment, the compound of the invention is:

wherein R⁹ is halogen. In an exemplary embodiment, the compound of theinvention is:

wherein each R⁹ is an independently selected halogen. In an exemplaryembodiment, the compound of the invention is H67 or H68 or a saltthereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted oxazolyl. In an exemplary embodiment, thecompound of the invention has a structure which is

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted alkyl oxazolyl. In an exemplary embodiment,the compound of the invention has a structure which is

wherein R¹⁰ is unsubstituted alkyl. In an exemplary embodiment, thecompound of the invention has a structure according to the followingformula:

wherein R¹⁰ is unsubstituted alkyl. In an exemplary embodiment, R¹⁰ isC₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, thecompound is H71 or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted isoxazolyl. In an exemplary embodiment, thecompound of the invention has a structure which is

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted alkyl isoxazolyl. In an exemplaryembodiment, the compound of the invention has a structure which is

wherein R¹⁰ is unsubstituted C₁-C₆ alkyl. In an exemplary embodiment,the compound of the invention has a structure according to the followingformula:

wherein R¹⁰ is unsubstituted alkyl. In an exemplary embodiment, R¹⁰ isunsubstituted C₁ alkyl. In an exemplary embodiment, R¹⁰ is unsubstitutedC₂ alkyl. In an exemplary embodiment, R¹⁰ is unsubstituted C₃ alkyl. Inan exemplary embodiment, R¹⁰ is unsubstituted C₄ alkyl. In an exemplaryembodiment, R¹⁰ is unsubstituted C₅ alkyl. In an exemplary embodiment,R¹⁰ is unsubstituted C₆ alkyl.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted thiazolyl. In an exemplary embodiment, thecompound of the invention has a structure which is

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted alkyl thiazolyl. In an exemplary embodiment,the compound of the invention has a structure which is:

wherein R¹⁰ is unsubstituted alkyl. In an exemplary embodiment, thecompound of the invention has a structure which is:

wherein R¹⁰ is unsubstituted alkyl. In an exemplary embodiment, R¹⁰ isC₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, thecompound is H72 or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted pyrazolyl. In an exemplary embodiment, thecompound of the invention has a structure which is

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is selected from the group consisting of unsubstituted alkylpyrrolyl, unsubstituted phenyl pyrrolyl and unsubstituted phenyl(unsubstituted alkyl)pyrrolyl. In an exemplary embodiment, the compoundof the invention has a structure which is:

wherein each R¹¹ is independently selected from unsubstituted C₁-C₆alkyl or phenyl. In an exemplary embodiment, the compound of theinvention has a structure which is

wherein each R¹¹ is independently selected from unsubstituted C₁-C₆alkyl or phenyl. In an exemplary embodiment, the compound of theinvention has a structure which is

In an exemplary embodiment, R¹¹ is unsubstituted C₁ alkyl. In anexemplary embodiment, R¹¹ is unsubstituted C₂ alkyl. In an exemplaryembodiment, R¹¹ is unsubstituted C₃ alkyl. In an exemplary embodiment,R¹¹ is unsubstituted C₄ alkyl. In an exemplary embodiment, R¹¹ isunsubstituted C₅ alkyl. In an exemplary embodiment, R¹¹ is unsubstitutedC₆ alkyl. In an exemplary embodiment, R¹¹ is unsubstituted phenyl. In anexemplary embodiment, the compound of the invention has a structureaccording to the following formula:

In an exemplary embodiment, the compound of the invention is H73 or asalt thereof. In an exemplary embodiment, the compound of the inventionis H74 or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted furanyl. In an exemplary embodiment, thecompound is:

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted alkylfuranyl. In an exemplary embodiment,the compound of the invention is:

wherein Y⁷ is unsubstituted alkyl, R* is a member selected from H and anegative charge. In another exemplary embodiment, R* is H. In anexemplary embodiment, Y⁷ is unsubstituted C₁ alkyl. In an exemplaryembodiment, Y⁷ is unsubstituted C₂ alkyl. In an exemplary embodiment, Y⁷is unsubstituted C₃ alkyl. In an exemplary embodiment, Y⁷ isunsubstituted C₄ alkyl. In an exemplary embodiment, Y⁷ is unsubstitutedC₅ alkyl. In an exemplary embodiment, Y⁷ is unsubstituted C₆ alkyl. Inan exemplary embodiment, the compound of the invention is H62 or a saltthereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted pyrrole. In an exemplary embodiment, thecompound is:

or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z³ is unsubstituted alkyl pyrrole. In an exemplary embodiment,the compound is:

wherein R¹⁰ is unsubstituted alkyl, or a salt thereof. In an exemplaryembodiment, the compound is:

wherein R¹⁰ is unsubstituted alkyl, or a salt thereof. In an exemplaryembodiment, R¹⁰ is unsubstituted C₁ alkyl. In an exemplary embodiment,R¹⁰ is unsubstituted C₂ alkyl. In an exemplary embodiment, R¹⁰ isunsubstituted C₃ alkyl. In an exemplary embodiment, R¹⁰ is unsubstitutedC₄ alkyl. In an exemplary embodiment, R¹⁰ is unsubstituted C₅ alkyl. Inan exemplary embodiment, R¹⁰ is unsubstituted C₆ alkyl. In an exemplaryembodiment, the compound is H69 or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of

or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of

or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z⁹ is unsubstituted alkyl. In an exemplary embodiment, Z⁹ isunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplaryembodiment, Z⁹ is methyl. In an exemplary embodiment, Z⁹ isunsubstituted C₄ alkyl. In an exemplary embodiment, Z⁹ is n-butyl orsec-butyl or isobutyl or tert-butyl. In an exemplary embodiment, Z⁹ istert-butyl.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein R¹⁵ is unsubstituted alkyl and R¹⁶ is H or phenyl substitutedalkyl. In an exemplary embodiment, R¹⁵ is unsubstituted C₁ or C₂ or C₃or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R¹⁵ isunsubstituted C₃ alkyl. In an exemplary embodiment, R¹⁶ is benzyl.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Z¹⁰ is hydroxy-substituted alkyl. In an exemplary embodiment,Z¹⁰ is hydroxysubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Y¹ is a halogen, Y is halo-substituted alkyl, R* is H or anegative charge. In an exemplary embodiment, Y is halo-substituted C₁-C₆alkyl. In another exemplary embodiment, R* is H. In an exemplaryembodiment, Y is fluoro-substituted C₁-C₆ alkyl, and Y¹ is as describedherein. In an exemplary embodiment, Y is trifluoro-substituted C₁-C₆alkyl, Y¹ is as described herein. In an exemplary embodiment, Y is C₁-C₆alkyl, substituted with one halogen, Y¹ is as described herein. In anexemplary embodiment, Y is C₁-C₆ alkyl, substituted with two halogens,Y¹ is as described herein. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with three halogens, Y¹ is as described herein. In anexemplary embodiment, Y is C₁-C₆ alkyl, substituted with four halogens,Y¹ is as described herein. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with one fluorine, Y¹ is as described herein. In anexemplary embodiment, Y is C₁-C₆ alkyl, substituted with two fluorines,Y¹ is as described herein. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with three fluorines, Y¹ is as described herein. In anexemplary embodiment, Y is C₁-C₆ alkyl, substituted with four fluorines,Y¹ is as described herein. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with one chlorine, Y¹ is as described herein. In anexemplary embodiment, Y is C₁-C₆ alkyl, substituted with two chlorines,Y¹ is as described herein. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with three chlorines, Y¹ is as described herein. In anexemplary embodiment, Y is C₁-C₆ alkyl, substituted with four chlorines,Y¹ is as described herein. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with a combination of two different halogens, Y¹ is asdescribed herein. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with at least one fluorine and at least one chlorine, Y¹ isas described herein. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with at least one fluorine and at least one bromine, Y¹ isas described herein. In an exemplary embodiment, Y is C₁-C₆ alkyl,substituted with at least one chlorine and at least one bromine, Y¹ isas described herein. In an exemplary embodiment, Y is fluoro-substitutedC₁-C₆ alkyl, and Y¹ is chloro. In an exemplary embodiment, Y istrifluoro-substituted C₁-C₆ alkyl, Y¹ is chloro. In an exemplaryembodiment, Y is fluoro-substituted C₁-C₆ alkyl, and Y¹ is fluoro. In anexemplary embodiment, Y is trifluoro-substituted C₁-C₆ alkyl, Y¹ isfluoro. In an exemplary embodiment, Y is fluoro-substituted C₁-C₆ alkyl,and Y¹ is bromo. In an exemplary embodiment, the compound of theinvention has a structure which is:

In an exemplary embodiment, the compound of the invention has astructure which is:

In an exemplary embodiment, the compound of the invention has astructure which is:

wherein Y¹ is as described herein.In an exemplary embodiment, the compound of the invention has astructure which is:

wherein Y¹ is as described herein.In an exemplary embodiment, the compound of the invention has astructure which is:

wherein Y¹ is as described herein.In an exemplary embodiment, the compound of the invention has astructure which is:

wherein Y is as described herein.In an exemplary embodiment, the compound of the invention has astructure which is:

wherein Y is as described herein.In an exemplary embodiment, the compound of the invention has astructure which is:

wherein Y is as described herein.In an exemplary embodiment, the compound of the invention has astructure which is:

wherein Y is as described herein.In an exemplary embodiment, the compound of the invention has astructure which is:

wherein Y is as described herein.In an exemplary embodiment, the compound of the invention has astructure which is:

wherein Y is as described herein.

In an exemplary embodiment, the compound of the invention has astructure which is H17 or a salt thereof. In an exemplary embodiment,the compound of the invention has a structure which is H18 or a saltthereof. In an exemplary embodiment, the compound of the invention has astructure which is H19 or a salt thereof. In an exemplary embodiment,the compound of the invention has a structure which is H20 or a saltthereof. In an exemplary embodiment, the compound of the invention has astructure which is H21 or a salt thereof. In an exemplary embodiment,the compound of the invention has a structure which is H22 or a saltthereof. In an exemplary embodiment, the compound of the invention has astructure which is H23 or a salt thereof.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is H or a negative charge, and R², R³, R⁴, R⁵ and R⁶ areaccording to the entries in the following table, or a salt thereof.

R² R³ R⁴ R⁵ R⁶ 182 CF₃ F H H H 183 CF₃ H F H H 184 CF₃ H H F H 185 CF₃ HH H F 186 F CF₃ H H H 187 H CF₃ F H H 188 H CF₃ H F H 189 H CF₃ H H F190 F H CF₃ H H 191 H F CF₃ H H 192 H H CF₃ F H 193 H H CF₃ H F 194 F HH CF₃ H 195 H F H CF₃ H 196 H H F CF₃ H 197 H H H CF₃ F 198 F H H H CF₃199 H F H H CF₃ 200 H H F H CF₃ 201 H H H F CF₃ 202 CF₃ Cl H H H 203 CF₃H Cl H H 204 CF₃ H H Cl H 205 CF₃ H H H Cl 206 Cl CF₃ H H H 207 H CF₃ ClH H 208 H CF₃ H Cl H 209 H CF₃ H H Cl 210 Cl H CF₃ H H 211 H Cl CF₃ H H212 H H CF₃ Cl H 213 H H CF₃ H Cl 214 Cl H H CF₃ H 215 H Cl H CF₃ H 216H H Cl CF₃ H 217 H H H CF₃ Cl 218 Cl H H H CF₃ 219 H Cl H H CF₃ 220 H HCl H CF₃ 221 H H H Cl CF₃ 222 CF₃ CF₃ H H H 223 CF₃ H CF₃ H H 224 CF₃ HH CF₃ H 225 CF₃ H H H CF₃ 226 H CF₃ CF₃ H H 227 H CF₃ H CF₃ H 228 H CF₃H H CF₃ 229 H H CF₃ CF₃ H 230 H H CF₃ H CF₃ 231 H H H CF₃ CF₃ 232 F F HH H 233 F H F H H 234 F H H F H 235 F H H H F 236 H F F H H 237 H F H FH 238 H F H H F 239 H H F F H 240 H H F H F 241 H H H F F 242 Cl Cl H HH 243 Cl H Cl H H 244 Cl H H Cl H 245 Cl H H H Cl 246 H Cl Cl H H 247 HCl H Cl H 248 H Cl H H Cl 249 H H Cl Cl H 250 H H Cl H Cl 251 H H H ClCl 252 F Cl H H H 253 F H Cl H H 254 F H H Cl H 255 F H H H Cl 256 H FCl H H 257 H F H Cl H 258 H F H H Cl 259 H H F Cl H 260 H H F H Cl 261 HH H F Cl 262 Cl F H H H 263 Cl H F H H 264 Cl H H F H 265 Cl H H H F 266H Cl F H H 267 H Cl H F H 268 H Cl H H F 269 H H Cl F H 270 H H Cl H F271 H H H Cl F 272 —CH₃ —CH₃ H H H 273 —CH₃ H —CH₃ H H 274 —CH₃ H H —CH₃H 275 —CH₃ H H H —CH₃ 276 H —CH₃ —CH₃ H H 277 H —CH₃ H —CH₃ H 278 H —CH₃H H —CH₃ 279 H H —CH₃ —CH₃ H 280 H H —CH₃ H —CH₃ 281 H H H —CH₃ —CH₃ 282—Y³ —CH₃ H H H 283 —Y³ H —CH₃ H H 284 —Y³ H H —CH₃ H 285 —Y³ H H H —CH₃286 H —Y³ —CH₃ H H 287 H —Y³ H —CH₃ H 288 H —Y³ H H —CH₃ 289 H H —Y³—CH₃ H 290 H H —Y³ H —CH₃ 291 H H H —Y³ —CH₃ 292 —CH₃ —Y³ H H H 293 —CH₃H —Y³ H H 294 —CH₃ H H —Y³ H 295 —CH₃ H H H —Y³ 296 H —CH₃ —Y³ H H 297 H—CH₃ H —Y³ H 298 H —CH₃ H H —Y³ 299 H H —CH₃ —Y³ H 300 H H —CH₃ H —Y³301 H H H —CH₃ —Y³ 302 —Y² —OCH₃ H H H 303 —Y² H —OCH₃ H H 304 —Y² H H—OCH₃ H 305 —Y² H H H —OCH₃ 306 H —Y² —OCH₃ H H 307 H —Y² H —OCH₃ H 308H —Y² H H —OCH₃ 309 H H —Y² —OCH₃ H 310 H H —Y² H —OCH₃ 311 H H H —Y²—OCH₃ 312 —OCH₃ —Y² H H H 313 —OCH₃ H —Y² H H 314 —OCH₃ H H —Y² H 315—OCH₃ H H H —Y² 316 H —OCH₃ —Y² H H 317 H —OCH₃ H —Y² H 318 H —OCH₃ H H—Y² 319 H H —OCH₃ —Y² H 320 H H —OCH₃ H —Y² 321 H H H —OCH₃ —Y² 322—OCH₃ —OCH₃ H H H 323 —OCH₃ H —OCH₃ H H 324 —OCH₃ H H —OCH₃ H 325 —OCH₃H H H —OCH₃ 326 H —OCH₃ —OCH₃ H H 327 H —OCH₃ H —OCH₃ H 328 H —OCH₃ H H—OCH₃ 329 H H —OCH₃ —OCH₃ H 330 H H —OCH₃ H —OCH₃ 331 H H H —OCH₃ —OCH₃332 —CH₃ —OCH₃ H H H 333 —CH₃ H —OCH₃ H H 334 —CH₃ H H —OCH₃ H 335 —CH₃H H H —OCH₃ 336 H —CH₃ —OCH₃ H H 337 H —CH₃ H —OCH₃ H 338 H —CH₃ H H—OCH₃ 339 H H —CH₃ —OCH₃ H 340 H H —CH₃ H —OCH₃ 341 H H H —CH₃ —OCH₃ 342—OCH₃ —CH₃ H H H 343 —OCH₃ H —CH₃ H H 344 —OCH₃ H H —CH₃ H 345 —OCH₃ H HH —CH₃ 346 H —OCH₃ —CH₃ H H 347 H —OCH₃ H —CH₃ H 348 H —OCH₃ H H —CH₃349 H H —OCH₃ —CH₃ H 350 H H —OCH₃ H —CH₃ 351 H H H —OCH₃ —CH₃ 352 —Y²—Y² H H H 353 —Y² H —Y² H H 354 —Y² H H —Y² H 355 —Y² H H H —Y² 356 H—Y² —Y² H H 357 H —Y² H —Y² H 358 H —Y² H H —Y² 359 H H —Y² H —Y² 360—Y³ —Y³ H H H 361 —Y³ H —Y³ H H 362 —Y³ H H —Y³ H 363 —Y³ H H H —Y³ 364H —Y³ —Y³ H H 365 H —Y³ H —Y³ H 366 H —Y³ H H —Y³ 367 H H —Y³ H —Y³ 368—Y² —Y³ H H H 369 —Y² H —Y³ H H 370 —Y² H H —Y³ H 371 —Y² H H H —Y³ 372H —Y² —Y³ H H 373 H —Y² H —Y³ H 374 H —Y² H H —Y³ 375 H H —Y² H —Y³ 376—Y³ —Y² H H H 377 —Y³ H —Y² H H 378 —Y³ H H —Y² H 379 —Y³ H H H —Y² 380H —Y³ —Y² H H 381 H —Y³ H —Y² H 382 H —Y³ H H —Y² 383 H H —Y³ H —Y²In an exemplary embodiment, for any of the entries in the above table,R^(c) is H. In an exemplary embodiment, for any of the entries in theabove table, R^(c) is methyl. In an exemplary embodiment, for any of theentries in the above table, R^(c) is ethyl. In an exemplary embodiment,for any of the entries in the above table, R^(c) is propyl.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein each Y¹ is independently selected halogen, Y is halo-substitutedC₁-C₆ alkyl, R* is H or a negative charge. In another exemplaryembodiment, R* is H. In an exemplary embodiment, Y is fluoro-substitutedC₁-C₆ alkyl, and each Y¹ is as described herein. In an exemplaryembodiment, Y is trifluoro-substituted C₁-C₆ alkyl, and each Y¹ is asdescribed herein. In an exemplary embodiment, Y is as described herein,and each Y¹ is as described herein. In an exemplary embodiment, Y isfluoro-substituted C₁-C₆ alkyl, and each Y¹ is chloro. In an exemplaryembodiment, Y is fluoro-substituted C₁-C₆ alkyl, and each Y¹ is fluoro.In an exemplary embodiment, Y is fluoro-substituted C₁-C₆ alkyl, a Y¹ isfluoro, and another Y¹ is chloro. In an exemplary embodiment, Y istrifluoro-substituted C₁-C₆ alkyl, and each Y¹ is chloro. In anexemplary embodiment, Y is trifluoro-substituted C₁-C₆ alkyl, and eachY¹ is fluoro. In an exemplary embodiment, Y is trifluoro-substitutedC₁-C₆ alkyl, a Y¹ is fluoro, and another Y¹ is chloro. In an exemplaryembodiment, the compound of the invention has a structure which isselected from the group consisting of

wherein each Y¹ and R* are as described herein.In an exemplary embodiment, the compound of the invention has astructure which is selected from the group consisting of

or a salt thereof. In an exemplary embodiment, the compound is H24 or asalt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein each Y¹ is a halogen, R* is H or a negative charge. In anotherexemplary embodiment, R* is H. In an exemplary embodiment, each Y¹ is asdescribed herein. In an exemplary embodiment, each Y¹ is fluoro. In anexemplary embodiment, each Y¹ is chloro. In an exemplary embodiment, oneY¹ is fluoro and another is Y¹ is chloro. In an exemplary embodiment,the compound of the invention is H11 or H12 or H13 or H14 or H15 or H16,or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein each Y is an independently selected halo-substituted C₁-C₆alkyl, R* is H or a negative charge. In another exemplary embodiment, R*is H. In an exemplary embodiment, each Y is as described herein. In anexemplary embodiment, one Y is fluoro-substituted C₁-C₆ alkyl, and theother Y is as described herein. In an exemplary embodiment, one Y istrifluoro-substituted C₁-C₆ alkyl and the other Y is as describedherein. In an exemplary embodiment, each Y is fluoro-substituted C₁-C₆alkyl. In an exemplary embodiment, each Y is trifluoro-substituted C₁-C₆alkyl. In an exemplary embodiment, the compound of the invention is H25or H26 or H27, or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein Y² is unsubstituted alkyl and Y³ is unsubstituted alkoxy, R* isH or a negative charge. In another exemplary embodiment, R* is H. In anexemplary embodiment, Y² is as described herein, and Y³ is as describedherein. In an exemplary embodiment, Y² is unsubstituted C₁-C₆ alkyl, andY³ is unsubstituted C₁-C₆ alkoxy. In an exemplary embodiment, Y² ismethyl, Y³ is as described herein. In an exemplary embodiment, Y² is asdescribed herein, Y³ is methoxy. In an exemplary embodiment, thecompound of the invention is H43, or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein each Y² is unsubstituted alkyl, and R* is H or a negativecharge. In another exemplary embodiment, R* is H. In an exemplaryembodiment, each Y² is as described herein. In an exemplary embodiment,Y² is unsubstituted C₁-C₆ alkyl. In an exemplary embodiment, one Y² ismethyl, and the other Y² is an unsubstituted alkyl aside from methyl. Inan exemplary embodiment, both Y² are methyl. In an exemplary embodiment,the compound of the invention is H43, or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure according to the following formula:

wherein each Y³ is independently selected unsubstituted alkoxy, R* is Hor a negative charge. In another exemplary embodiment, R* is H. In anexemplary embodiment, each Y³ is as described herein. In an exemplaryembodiment, Y³ is unsubstituted C₁-C₆ alkoxy, and Y³ is unsubstitutedC₁-C₆ alkoxy. In an exemplary embodiment, a Y³ is methoxy, and anotherY³ is as described herein. In an exemplary embodiment, the compound ofthe invention is H38 or H39 or H40, or a salt thereof.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is H or a negative charge, and R², R³, R⁴, R⁵ and R⁶ areaccording to the entries in the following table, or a salt thereof.

R² R³ R⁴ R⁵ R⁶ 384 —OCH₃ —OCH₃ —OCH₃ H H 385 —OCH₃ —OCH₃ H —OCH₃ H 386—OCH₃ —OCH₃ H H —OCH₃ 387 —OCH₃ H —OCH₃ H —OCH₃ 388 —OCH₃ H —OCH₃ —OCH₃H 389 H —OCH₃ —OCH₃ —OCH₃ H 390 H —OCH₃ H —OCH₃ —OCH₃ 391 H H —OCH₃—OCH₃ —OCH₃ 392 —CF₃ —Y¹ —Y¹ H H 393 —CF₃ —Y¹ H —Y¹ H 394 —CF₃ —Y¹ H H—Y¹ 395 —CF₃ H —Y¹ H —Y¹ 396 —CF₃ H —Y¹ —Y¹ H 397 H —CF₃ —Y¹ —Y¹ H 398 H—CF₃ H —Y¹ —Y¹ 399 H H —CF₃ —Y¹ —Y¹ 400 —Y¹ —CF₃ —Y¹ H H 401 —Y¹ —CF₃ H—Y¹ H 402 —Y¹ —CF₃ H H —Y¹ 403 —Y¹ H —CF₃ H —Y¹ 404 —Y¹ H —CF₃ —Y¹ H 405H —Y¹ —CF₃ —Y¹ H 406 H —Y¹ H —CF₃ —Y¹ 407 H H —Y¹ —CF₃ —Y¹ 408 —Y¹ —Y¹—CF₃ H H 409 —Y¹ —Y¹ H —CF₃ H 410 —Y¹ —Y¹ H H —CF₃ 411 —Y¹ H —Y¹ H —CF₃412 —Y¹ H —Y¹ —CF₃ H 413 H —Y¹ —Y¹ —CF₃ H 414 H —Y¹ H —Y¹ —CF₃ 415 H H—Y¹ —Y¹ —CF₃ 416 —Y¹ —Y¹ —CF₃ H H 417 —Y¹ —Y¹ H —CF₃ H 418 —Y¹ —Y¹ H H—CF₃ 419 —Y¹ H —Y¹ H —CF₃ 420 —Y¹ H —Y¹ —CF₃ H 421 H —Y¹ —Y¹ —CF₃ H 422H —Y¹ H —Y¹ —CF₃ 423 H H —Y¹ —Y¹ —CF₃

In an exemplary embodiment, the compound of the invention has thefollowing structure:

wherein n is an integer from 0 to 5, each X is an independently selectedhalogen, R* is selected from the group consisting of H, a negativecharge and a positively charged counterion, and L is selected from thegroup consisting of —S—, —S(O)—, —SO₂—, —O—, —C(O)—, —C(OH)—, ″—CH₂O—′,″—CH₂NH—′, ″—C(O)NH—′, ″—NHC(O)—′, ″—NHC(O)O—′, and —CH₂—, wherein ″indicates a covalent linkage between L and the phenyl ring, and wherein′ indicates a covalent linkage between L and the boron-containingmoiety, or a salt thereof.

In an exemplary embodiment, n is 0 and L is selected from the groupconsisting of —S(O)—, —SO₂—, —C(O)—, —C(OH)—, ″—CH₂O—′, ″—NHC(O)O—′ and—CH₂—, wherein ″ indicates a covalent linkage between L and the phenylring, and wherein indicates a covalent linkage between L and theboron-containing moiety. In an exemplary embodiment, n is 0 and L is″—NHC(O)—′, wherein ″ indicates a covalent linkage between L and thephenyl ring, and wherein ′ indicates a covalent linkage between L andthe boron-containing moiety. In another exemplary embodiment, R* is H.

In an exemplary embodiment, n is 1 and L is selected from the groupconsisting of —S—, —S(O)— and —SO₂—, and there is a proviso that thecompound is not

In an exemplary embodiment, there is a proviso that the compound is not

In an exemplary embodiment, n is 2 and L is selected from the groupconsisting of —S—, —S(O)— and —SO₂—. In an exemplary embodiment, n is 2,X is Cl and L is selected from the group consisting of —S—, —S(O)— and—SO₂—. In an exemplary embodiment, n is 2, X is F and L is selected fromthe group consisting of —S—, —S(O)— and —SO₂—. In an exemplaryembodiment, n is 2, each X is F or Cl, wherein at least one X is Cl, andL is selected from the group consisting of —S—, —S(O)— and —SO₂—.

In an exemplary embodiment, n is 3 and L is selected from the groupconsisting of —S—, —S(O)— and —SO₂—. In an exemplary embodiment, n is 4and L is selected from the group consisting of —S—, —S(O)— and —SO₂—. Inan exemplary embodiment, n is 5 and L is selected from the groupconsisting of —S—, —S(O)— and —SO₂—.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is selected from the group consisting of H, a negative chargeand a positively charged counterion, L is selected from the groupconsisting of —S—, —S(O)—, —SO₂—, —O—, —C(O)—, —C(OH)—, ″—CH₂O—′,″—CH₂NH—′, ″—C(O)NH—′, ″—NHC(O)—′, ″—NHC(O)O—′, and —CH₂—, wherein ″indicates a covalent linkage between L and the phenyl ring, and wherein′ indicates a covalent linkage between L and the boron-containingmoiety, and R², R³, R⁴, R⁵ and R⁶ are members selected from thefollowing table, or a salt thereof. In an exemplary embodiment, L is—S—, and R², R³, R⁴, R⁵ and R⁶ are members selected from the followingtable. In an exemplary embodiment, L is —S(O)—, and R², R³, R⁴, R⁵ andR⁶ are members selected from the following table. In an exemplaryembodiment, L is —SO₂—, and R², R³, R⁴, R⁵ and R⁶ are according to theentries in the following table, or a salt thereof

R² R³ R⁴ R⁵ R⁶ 424 Cl H H H H 425 H Cl H H H 426 H H Cl H H 427 Cl Cl HH H 428 Cl H Cl H H 429 Cl H H Cl H 430 Cl H H H Cl 431 H Cl Cl H H 432H Cl H Cl H 433 Cl Cl Cl H H 434 Cl Cl H Cl H 435 Cl Cl H H Cl 436 Cl HCl H Cl 437 H Cl Cl Cl H 438 Cl Cl Cl Cl H 439 Cl Cl Cl H Cl 440 Cl Cl HCl Cl 441 Cl Cl Cl Cl Cl 442 F H H H H 443 H F H H H 444 H H F H H 445 FF H H H 446 F H F H H 447 F H H F H 448 F H H H F 449 H F F H H 450 H FH F H 451 F F F H H 452 F F H F H 453 F F H H F 454 F H F H F 455 H F FF H 456 F F F F H 457 F F F H F 458 F F H F F 459 F F F F F 460 Cl F H HH 461 F Cl H H H 462 Cl H F H H 463 F H Cl H H 464 Cl H H F H 465 F H HCl H 466 Cl H H H F 467 F H H H Cl 468 H Cl F H H 469 H F Cl H H 470 HCl H F H 471 H F H Cl H 472 Cl F F H H 473 F Cl F H H 474 F F Cl H H 475Cl Cl F H H 476 F Cl Cl H H 477 Cl F Cl H H 478 Cl F H F H 479 F Cl H FH 480 F F H Cl H 481 Cl Cl H F H 482 Cl F H Cl H 483 F Cl H Cl H 485 ClF H H F 486 F Cl H H F 487 F F H H Cl 488 Cl Cl H H F 489 Cl F H H Cl490 F Cl H H Cl 491 Cl H F H F 492 F H Cl H F 493 Cl H Cl H F 494 Cl H FH Cl 495 H Cl F F H 496 H F Cl F H 497 H Cl Cl F H 498 H Cl F Cl H 499Cl F F F H 500 F Cl F F H 501 F F Cl F H 502 F F F Cl H 503 Cl Cl F F H504 Cl F Cl F H 505 Cl F F Cl H 506 F Cl Cl F H 507 F Cl Cl Cl H 508 ClF Cl Cl H 509 Cl Cl F Cl H 510 Cl Cl Cl F H 511 F F F F H 512 Cl F F H F513 F Cl F H F 514 F F Cl H F 515 F F F H Cl 516 Cl Cl F H F 517 Cl F ClH F 518 Cl F F H Cl 519 F Cl Cl H F 520 F F Cl H Cl 521 Cl Cl Cl H F 522Cl Cl F H Cl 523 Cl F Cl H Cl 524 F Cl Cl H Cl 525 Cl F H F F 526 F Cl HF F 527 Cl Cl H F F 528 Cl F H Cl F 529 Cl F H F Cl 530 F Cl H Cl F 531Cl Cl H Cl F 532 Cl Cl H F Cl 533 F Cl Cl Cl Cl 534 Cl F Cl Cl Cl 535 ClCl F Cl Cl 536 F F Cl Cl Cl 537 F Cl F Cl Cl 538 F Cl Cl F Cl 539 F ClCl Cl F 540 Cl F Cl F Cl 541 Cl Cl F F Cl 542 F F F Cl Cl 543 F F Cl FCl 544 F Cl F F Cl 546 Cl F F F Cl 547 F Cl F Cl F 548 F Cl Cl F F 549Cl F F F F 550 F Cl F F F 551 F F Cl F F

In an exemplary embodiment, the compound of the invention has thefollowing structure:

wherein Y is either halo-substituted C₁-C₆ alkyl or unsubstituted C₁-C₆alkyl, and R* is selected from the group consisting of H, a negativecharge and a positively charged counterion, L is selected from the groupconsisting of —S—, —S(O)—, —SO₂—, —O—, —C(O)—, —C(OH)—, ″—CH₂O—′,″—CH₂NH—′, ″—C(O)NH—′, ″—NHC(O)—′, ″—NHC(O)O—′, and —CH₂—, wherein ″indicates a covalent linkage between L and the phenyl ring, and wherein′ indicates a covalent linkage between L and the boron-containingmoiety, or a salt thereof. In an exemplary embodiment, L is ″—C(O)NH—′or ″—NHC(O)—′.

In an exemplary embodiment, the compound has the following structure:

In an exemplary embodiment, the compound has the proviso that thecompound is not

In an exemplary embodiment, the compound has structure which is

In an exemplary embodiment, the compound has structure which is

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R², R³, R⁴, R⁵ and R⁶ are members selected from the followingtable, or a salt thereof

R² R³ R⁴ R⁵ R⁶ 552 H H H H H 553 NO₂ H H H H 554 H NO₂ H H H 555 H H NO₂H H 556 H H H NO₂ H 557 H H H H NO₂ 558 C(O)OR²⁰ H H H H 559 H C(O)OR²⁰H H H 560 H H C(O)OR²⁰ H H 561 H H H C(O)OR²⁰ H 562 H H H H C(O)OR²⁰ 563C(O)OCH₃ H H H H H C(O)OCH₃ H H H 564 H H C(O)OCH₃ H H 565 H H HC(O)OCH₃ H 566 H H H H C(O)OCH₃ 567 OR²⁰ H H H H 568 H OR²⁰ H H H 569 HH OR²⁰ H H 570 H H H OR²⁰ H 571 H H H H OR²⁰ 572 OCH₃ H H H H 573 H OCH₃H H H 574 H H OCH₃ H H 575 H H H OCH₃ H 576 H H H H OCH₃ 577 NR²¹R²² H HH H 578 H NR²¹R²² H H H 579 H H NR²¹R²² H H 580 H H H NR²¹R²² H 581 H HH H NR²¹R²² 582 NHR²² H H H H 583 H NHR²² H H H 584 H H NHR²² H H 585 HH H NHR²² H 586 H H H H NHR²² 587 NHC(O)R¹⁵ H H H H 588 H NHC(O)R¹⁵ H HH 589 H H NHC(O)R¹⁵ H H 590 H H H NHC(O)R¹⁵ H 591 H H H H NHC(O)R¹⁵ 592NH₂ H H H H 593 H NH₂ H H H 594 H H NH₂ H H 595 H H H NH₂ H 596 H H H HNH₂For the respective entries in this table, R²⁰ is unsubstituted alkyl.For the respective entries in this table, R²¹ is H or unsubstitutedalkyl. For the respective entries in this table, R²² is H orunsubstituted alkyl. In an exemplary embodiment, R¹⁵ in NHC(O)R¹⁵ isselected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted phenyl and substituted orunsubstituted cyclohexyl. In an exemplary embodiment, R¹⁵ in NHC(O)R¹⁵is selected from the group consisting of unsubstituted alkyl,haloalkylsubstituted phenyl, unsubstituted phenyl and unsubstitutedcyclohexyl. In an exemplary embodiment, R¹⁵ in NHC(O)R¹⁵ is selectedfrom the group consisting of methyl, trifluoromethylsubstitutedphenyl,unsubstituted phenyl and unsubstituted cyclohexyl. In an exemplaryembodiment, R¹⁵ in NHC(O)R¹⁵ is selected from the group consisting ofmethyl, halosubstitutedphenyl, alkoxy substitutedphenyl,trifluoromethylsubstitutedphenyl, unsubstituted phenyl and unsubstitutedcyclohexyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R¹⁵ is selected from the group consisting of methyl,halosubstitutedphenyl, alkoxy substitutedphenyl, trifluoromethylsubstitutedphenyl, unsubstituted phenyl and unsubstituted cyclohexyl. Inan exemplary embodiment, R¹⁵ is selected from the group consisting ofortho-trifluoromethylsubstitutedphenyl,meta-trifluoromethylsubstitutedphenyl andpara-trifluoromethylsubstitutedphenyl. In an exemplary embodiment, R¹⁵is para-trifluoromethylsubstitutedphenyl. In an exemplary embodiment,R¹⁵ is selected from the group consisting ofortho-halosubstitutedphenyl, meta-halosubstitutedphenyl andpara-halosubstitutedphenyl. In an exemplary embodiment, R¹⁵ isortho-fluorophenyl. In an exemplary embodiment, R¹⁵ ismeta-fluorophenyl. In an exemplary embodiment, R¹⁵ is para-fluorophenyl.In an exemplary embodiment, R¹⁵ is ortho-chlorophenyl. In an exemplaryembodiment, R¹⁵ is meta-chlorophenyl. In an exemplary embodiment, R¹⁵ ispara-chlorophenyl. In an exemplary embodiment, R¹⁵ isortho-alkoxyphenyl. In an exemplary embodiment, R¹⁵ ismeta-alkoxyphenyl. In an exemplary embodiment, R¹⁵ is para-alkoxyphenyl.In an exemplary embodiment, R¹⁵ is ortho-methoxyphenyl. In an exemplaryembodiment, R¹⁵ is meta-methoxyphenyl. In an exemplary embodiment, R¹⁵is para-methoxyphenyl.

In an exemplary embodiment, the compound of the invention is

wherein R²⁵ is unsubstituted linear alkylene, and R²⁶ is halosubstitutedaryl. In an exemplary embodiment, R²⁵ is unsubstituted linear alkylene,and R²⁶ is monohaloaryl. In an exemplary embodiment, R²⁵ isunsubstituted linear alkylene, and R²⁶ is 4-haloaryl. In an exemplaryembodiment, R²⁵ is unsubstituted linear alkylene, and R²⁶ is 3-haloaryl.In an exemplary embodiment, R²⁵ is unsubstituted linear alkylene, andR²⁶ is 2-haloaryl. In an exemplary embodiment, R²⁵ is methylene, and R²⁶is 4-haloaryl. In an exemplary embodiment, R²⁵ is methylene, and R²⁶ is3-haloaryl. In an exemplary embodiment, R²⁵ is methylene, and R²⁶ is2-haloaryl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is selected from the group consisting of H, a negative chargeand a positively charged counterion, and R², R³, R⁴, R⁵ and R⁶ aremembers selected from the following table, or a salt thereof.

R² R³ R⁴ R⁵ R⁶ 597 Cl H H H H 598 H Cl H H H 599 H H Cl H H 600 Cl Cl HH H 601 Cl H Cl H H 602 Cl H H Cl H 603 Cl H H H Cl 604 H Cl Cl H H 605H Cl H Cl H 606 Cl Cl Cl H H 607 Cl Cl H Cl H 608 Cl Cl H H Cl 609 Cl HCl H Cl 610 H Cl Cl Cl H 611 Cl Cl Cl Cl H 612 Cl Cl Cl H Cl 613 Cl Cl HCl Cl 614 Cl Cl Cl Cl Cl 615 F H H H H 616 H F H H H 617 H H F H H 618 FF H H H 619 F H F H H 620 F H H F H 621 F H H H F 622 H F F H H 623 H FH F H 624 F F F H H 625 F F H F H 626 F F H H F 627 F H F H F 628 H F FF H 629 F F F F H 630 F F F H F 631 F F H F F 632 F F F F F

In an exemplary embodiment, the compound has a structure which is

or a salt thereof. In an exemplary embodiment, the compound has astructure which is

or a salt thereof.

In an exemplary embodiment, the compound of the invention has astructure which is

or salts thereof. In an exemplary embodiment, the compound of theinvention has a structure which is

In an exemplary embodiment, the compound of the invention has astructure which is

or salts thereof. In an exemplary embodiment, the compound of theinvention has a structure which is

In an exemplary embodiment, the compound of the invention is

wherein R²⁷ is selected from the group consisting of unsubstitutedindolyl, unsubstituted benzothiooxazolyl, and halosubstituted orunsubstituted pyrimidinyl.

In an exemplary embodiment, the compound of the invention is

wherein R²⁷ is unsubstituted pyrimidinyl. In an exemplary embodiment,the compound is

In an exemplary embodiment, the compound of the invention is

wherein R²⁷ is halosubstituted pyrimidinyl. In an exemplary embodiment,R²⁷ is monohalosubstituted pyrimidinyl. In an exemplary embodiment, R²⁷is chlorosubstituted pyrimidinyl. In an exemplary embodiment, thecompound is

wherein R²⁸ is selected from the group consisting of F, Cl, Br and I. Inan exemplary embodiment, the compound is

wherein R²⁸ is selected from the group consisting of F, Cl, Br and I. Inan exemplary embodiment, the compound is

wherein R²⁸ is selected from the group consisting of F, Cl, Br and I. Inan exemplary embodiment, R²⁸ is F. In an exemplary embodiment, thecompound is

In an exemplary embodiment, the compound of the invention is

wherein R²⁷ is unsubstituted indolyl. In an exemplary embodiment, thecompound is

In an exemplary embodiment, the compound of the invention is

wherein R²⁷ is unsubstituted indolyl. In an exemplary embodiment, thecompound is

In an exemplary embodiment, the cytotoxicity on murine L929 IC50 of acompound of the invention is a member selected from about 1 μM to 20 μM.In an exemplary embodiment, the cytotoxicity on murine L929 IC50 of acompound of the invention is a member selected from about 10 μM to 15μM.

In an exemplary embodiment, the selectivity index (SI) of a compound ofthe invention is between about 50-150. In an exemplary embodiment, theselectivity index (SI) ofN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamideis between about 75-100. In an exemplary embodiment, the selectivityindex (SI) of 6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-olis greater than about 75-100.

In an exemplary embodiment, the in vitro metabolism T1/2 (Mouse/humanliver microsomes) of a compound of the invention is a member selectedfrom about 300 minutes to 400 minutes. In an exemplary embodiment, thein vitro metabolism T1/2 (Mouse/human liver microsomes) of a compound ofthe invention is a member selected from about 340 minutes to 360minutes. In an exemplary embodiment, the in vitro metabolism T1/2(Mouse/human liver microsomes) ofN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamideis a member selected from about 340 minutes to 360 minutes. In anexemplary embodiment, the in vitro metabolism T1/2 (Mouse/human livermicrosomes) of 6-(4-chlorophenyl sulfinyl)benzo[c][1,2]oxaborol-1(3H)-olis greater than 350 minutes.

In an exemplary embodiment, the in vitro metabolism T1/2 (Mouse S9) of acompound of the invention is a member selected from about 100 minutes to300 minutes. In an exemplary embodiment, the in vitro metabolism T1/2(Mouse S9) ofN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamideis a member selected from about 200 minutes to 225 minutes.

In an exemplary embodiment, a compound of the invention essentially doesnot inhibit a cytochrome P450 enzyme. In an exemplary embodiment, acompound of the invention does not inhibit a cytochrome P450 enzyme. Inan exemplary embodiment,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamideessentially does not inhibit a cytochrome P450 enzyme. In an exemplaryembodiment,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamidedoes not inhibit a cytochrome P450 enzyme. In an exemplary embodiment,6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol essentiallydoes not inhibit a cytochrome P450 enzyme. In an exemplary embodiment,6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol does notinhibit a cytochrome P450 enzyme. In an exemplary embodiment, thecytochrome P450 enzyme is a member selected from CP1A2, 2C9, 2D6 and3A4. In an exemplary embodiment, the cytochrome P450 enzyme is CYP2C19.

In an exemplary embodiment, a compound of the invention is essentiallynot a substrate for the P-gp transporter. In an exemplary embodiment, acompound of the invention is not a substrate for the P-gp transporter.In an exemplary embodiment,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamideis essentially not a substrate for the P-gp transporter. In an exemplaryembodiment,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamideis not a substrate for the P-gp transporter.

In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asalt thereof. In an exemplary embodiment, the salt is a pharmaceuticallyacceptable salt. In an exemplary embodiment, the invention provides acompound described herein, or a hydrate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asolvate thereof. In an exemplary embodiment, the invention provides acompound described herein, or a prodrug thereof. In an exemplaryembodiment, the invention provides a salt of a compound describedherein. In an exemplary embodiment, the invention provides apharmaceutically acceptable salt of a compound described herein. In anexemplary embodiment, the invention provides a hydrate of a compounddescribed herein. In an exemplary embodiment, the invention provides asolvate of a compound described herein. In an exemplary embodiment, theinvention provides a prodrug of a compound described herein.

In an exemplary embodiment, alkyl is linear alkyl. In another exemplaryembodiment, alkyl is branched alkyl.

In an exemplary embodiment, heteroalkyl is linear heteroalkyl. Inanother exemplary embodiment, heteroalkyl is branched heteroalkyl.

III.b) Compositions Involving Stereoisomers

As used herein, the term “chiral”, “enantiomerically enriched” or“diastereomerically enriched” refers to a composition having anenantiomeric excess (ee) or a diastereomeric excess (de) of greater thanabout 50%, preferably greater than about 70% and more preferably greaterthan about 90%. In general, higher than about 90% enantiomeric ordiastereomeric excess is particularly preferred, e.g., thosecompositions with greater than about 95%, greater than about 97% andgreater than about 99% ee or de.

When a first compound and a second compound are present in acomposition, and the first compound is a non-superimposable mirror imageof the second compound, and the first compound is present in thecomposition in a greater amount than the second compound, then the firstcompound is referred to herein as being present in “enantiomericexcess”.

The term “enantiomeric excess” of a compound z, as used herein, isdefined as:

${ee}_{z} = {\left( \frac{{{{conc}.\mspace{14mu}{of}}\mspace{14mu} z} - {{{conc}.\mspace{14mu}{of}}\mspace{14mu} y}}{{{{conc}.\mspace{14mu}{of}}\mspace{14mu} z} + {{{conc}.\mspace{14mu}{of}}\mspace{14mu} y}} \right) \times 100}$wherein z is a first compound in a composition, y is a second compoundin the composition, and the first compound is a non-superimposablemirror image of the second compound.

The term “enantiomeric excess” is related to the older term “opticalpurity” in that both are measures of the same phenomenon. The value ofee will be a number from 0 to 100, zero being racemic and 100 beingenantiomerically pure. A composition which in the past might have beencalled 98% optically pure is now more precisely characterized by 96% ee.A 90% ee reflects the presence of 95% of one enantiomer and 5% of theother(s) in the material in question.

When a first compound and at least one additional compound are presentin a composition, and the first compound and each of the additionalcompounds are stereoisomers, but not mirror images, of one another, andthe first compound is present in the composition in a greater amountthan each of the additional compounds, then the first compound isreferred to herein as being present in “diastereomeric excess”.

When dealing with mixtures of diastereomers, the term “diastereomericexcess” or “de” is defined analogously to enantiomeric excess. Thus:

${de}_{w} = {\left( \frac{\begin{matrix}{{{{conc}.\mspace{14mu}{of}}\mspace{14mu}{major}\mspace{14mu}{diastereomer}} -} \\{{{conc}.\mspace{14mu}{of}}\mspace{14mu}{minor}\mspace{14mu}{{diastereomer}(s)}}\end{matrix}}{\begin{matrix}{{{{conc}.\mspace{14mu}{of}}\mspace{14mu}{major}\mspace{14mu}{diastereomer}} +} \\{{{conc}.\mspace{14mu}{of}}\mspace{14mu}{minor}\mspace{14mu}{{diastereomer}(s)}}\end{matrix}} \right) \times 100}$wherein the major diastereomer is a first compound in a composition, andthe minor diastereomer(s) is at least one additional compound in thecomposition, and the major diastereomer and minor diastereomer(s) arestereoisomers, but not mirror images, of one another.

The value of de will likewise be a number from 0 to 100, zero being anequal mixture of a first diastereomer and the remaining diastereomer(s),and 100 being 100% of a single diastereomer and zero % of theother(s)—i.e. diastereomerically pure. Thus, 90% de reflects thepresence of 95% of one diastereomer and 5% of the other diastereomer(s)in the material in question.

Hence, in one embodiment, the invention provides a composition includinga first compound of the invention, wherein the first compound of theinvention has at least one stereocenter, and at least one stereoisomerof the first compound of the invention. In another embodiment, theinvention provides a composition including a first compound of theinvention, wherein the first compound of the invention has at least onestereocenter, and a second compound of the invention, wherein the firstcompound of the invention is a stereoisomer of the second compound ofthe invention. In another embodiment, the invention provides acomposition including a first compound of the invention, wherein thefirst compound of the invention has at least one stereocenter, and onlyone stereoisomer of the first compound of the invention.

In another embodiment, the invention provides a composition including afirst compound of the invention, wherein the first compound of theinvention has only one stereocenter, and an enantiomer of the firstcompound of the invention. In another embodiment, the invention providesa composition including a first compound of the invention, wherein thefirst compound of the invention has two stereocenters, and an enantiomerof the first compound of the invention. In another embodiment, theinvention provides a composition including a first compound of theinvention, wherein the first compound of the invention has twostereocenters, and at least one diastereomer of the first compound ofthe invention. In another embodiment, the invention provides acomposition including a first compound of the invention, wherein thefirst compound of the invention has two stereocenters, and only onediastereomer of the first compound of the invention.

In situations where the first compound of the invention and itsenantiomer are present in a composition, the first compound of theinvention can be present in an enantiomeric excess of at least about80%, or at least about 90%, or at least about 92% or at least about 95%.In another embodiment, where the first compound of the invention and itsenantiomer are present in a composition, the first compound of theinvention can be present in an enantiomeric excess of at least about96%, at least about 97%, at least about 98%, at least about 99% or atleast about 99.5%. In another embodiment, the first compound of theinvention has at least one stereocenter and is enantiomerically pure(enantiomeric excess is about 100%).

In situations where the first compound of the invention and at least onediastereomer of the first compound of the invention are present in acomposition, the first compound of the invention can be present in adiastereomeric excess of at least about 80%, or at least about 90%, orat least about 92% or at least about 95%. In situations where the firstcompound of the invention and at least one diastereomer of the firstcompound of the invention are present in a composition, the firstcompound of the invention can be present in a diastereomeric excess ofat least about 96%, at least about 97%, at least about 98%, at leastabout 99% or at least about 99.5%. In another embodiment, the firstcompound of the invention has at least two stereocenters and isdiastereomerically pure (diastereomeric excess is about 100%).

Enantiomeric or diastereomeric excess can be determined relative toexactly one other stereoisomer, or can be determined relative to the sumof at least two other stereoisomers. In an exemplary embodiment,enantiomeric or diastereomeric excess is determined relative to allother detectable stereoisomers, which are present in the mixture.Stereoisomers are detectable if a concentration of such stereoisomer inthe analyzed mixture can be determined using common analytical methods,such as chiral HPLC.

As used herein, and unless otherwise indicated, a composition that is“substantially free” of a compound means that the composition containsless than about 20% by weight, or less than about 15% by weight, or lessthan about 10% by weight, or less than about 5% by weight, or less thanabout 3% by weight, or less than about 2% by weight, or less than about1% by weight of the compound.

As used herein, the term “substantially free of the (or its) enantiomer”means that a composition contains a significantly greater proportion ofa first compound of the invention than a second compound of theinvention, wherein the first compound is a non-superimposable mirrorimage of the second compound. In one embodiment of the invention, theterm “substantially free of the enantiomer” means that the compositionis made up of at least about 90% by weight of a first compound of theinvention, and about 10% by weight or less of a second compound of theinvention, wherein the first compound is a non-superimposable mirrorimage of the second compound. In one embodiment of the invention, theterm “substantially free of the (R) enantiomer” means that thecomposition is made up of at least about 90% by weight of a firstcompound of the invention which has only one stereocenter and thestereocenter is in an (S) configuration, and about 10% by weight or lessof a second compound of the invention, wherein the second compound isthe enantiomer of the first compound. In one embodiment of theinvention, the term “substantially free of the enantiomer” means thatthe composition is made up of at least about 95% by weight of a firstcompound of the invention, and about 5% by weight or less of a secondcompound of the invention, wherein the first compound is anon-superimposable mirror image of the second compound. In oneembodiment of the invention, the term “substantially free of the (R)enantiomer” means that the composition is made up of at least about 95%by weight of a first compound of the invention which has only onestereocenter and the stereocenter is in an (S) configuration, and about5% by weight or less of a second compound of the invention, wherein thesecond compound is the enantiomer of the first compound. In oneembodiment of the invention, the term “substantially free of theenantiomer” means that the composition is made up of at least about 98%by weight of a first compound of the invention, and about 2% by weightor less of a second compound of the invention, wherein the firstcompound is a non-superimposable mirror image of the second compound. Inone embodiment of the invention, the term “substantially free of the (R)enantiomer” means that the composition is made up of at least about 98%by weight of a first compound of the invention which has only onestereocenter and the stereocenter is in an (S) configuration, and about2% by weight or less of a second compound of the invention, wherein thesecond compound is the enantiomer of the first compound. In oneembodiment of the invention, the term “substantially free of theenantiomer” means that the composition is made up of at least about 99%by weight of a first compound of the invention, and about 1% by weightor less of a second compound of the invention, wherein the firstcompound is a non-superimposable mirror image of the second compound. Inone embodiment of the invention, the term “substantially free of the (R)enantiomer” means that the composition is made up of at least about 99%by weight of a first compound of the invention which has only onestereocenter and the stereocenter is in an (S) configuration, and about1% by weight or less of a second compound of the invention, wherein thesecond compound is the enantiomer of the first compound.

III.b) Combinations Comprising Additional Therapeutic Agents

The compounds of the invention may also be used in combination withadditional therapeutic agents. The invention thus provides, in a furtheraspect, a combination comprising a compound described herein or apharmaceutically acceptable salt thereof together with at least oneadditional therapeutic agent. In an exemplary embodiment, the additionaltherapeutic agent is a compound of the invention. In an exemplaryembodiment, the additional therapeutic agent includes a boron atom. Inan exemplary embodiment, the additional therapeutic agent does notcontain a boron atom.

When a compound of the invention is used in combination with a secondtherapeutic agent active against the same disease state, the dose ofeach compound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart. It will be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian. In an exemplary embodiment, the additional therapeuticagent is Berenil. In an exemplary embodiment, the additional therapeuticagent is an antiprotozoa. In an exemplary embodiment, the additionaltherapeutic agent is a member selected from Benznidazole, Buparvaquone,Carbarsone, Clioquinol, Disulfuram, Eflornithine, Emetine, Etofamide,Furazolidone, Meglumine antimonate, Melarsoprol, Metronidazole,Miltefosine, Nifurtimox, Nimorazole, Nitazoxanide, Ornidazole,Paromomycin sulfate, Pentamidine, Pyrimethamine, Secnidazole andTinidazole. In an exemplary embodiment, the additional therapeutic agentis pentamidine. In an exemplary embodiment, the additional therapeuticagent is suramin. In an exemplary embodiment, the additional therapeuticagent is Eflornithine. In an exemplary embodiment, the additionaltherapeutic agent is Melarsoprol. In an exemplary embodiment, theadditional therapeutic agent is Nifurtimox. In an exemplary embodiment,the additional therapeutic agent is an antiparasitic. In an exemplaryembodiment, the additional therapeutic agent is a member selected fromAmitraz, Avermectin, Carbadox, Diethylcarbamazine, Dimetridazole,Diminazene, Ivermectin, Macrofilaricide, Malathion, Mitaban,Organophosphate, Oxamniquine, Permethrin, Praziquantel, Pyrantelpamoate, Selamectin, Sodium stibogluconate and Thiabendazole. In anexemplary embodiment, the additional therapeutic agent is a memberselected from antimony, meglumine antimonate, sodium stibogluconate,amphotericin, miltefosine and paromomycin.

The compounds of the invention, or pharmaceutical formulations thereofmay also be used in combination with other therapeutic agents, forexample immune therapies [e.g. interferon, such as interferon alfa-2a(ROFERON®-A; Hoffmann-La Roche), interferon alpha-2b (INTRON®-A;Schering-Plough), interferon alfacon-1 (INFERGEN®; Intermune),peginterferon alpha-2b (PEGINTRON™; Schering-Plough) or peginterferonalpha-2a (PEGASYS®; Hoffmann-La Roche)], therapeutic vaccines,antifibrotic agents, anti-inflammatory agents [such as corticosteroidsor NSAIDs], bronchodilators [such as beta-2 adrenergic agonists andxanthines (e.g. theophylline)], mucolytic agents, anti-muscarinics,anti-leukotrienes, inhibitors of cell adhesion [e.g. ICAM antagonists],anti-oxidants [e.g. N-acetylcysteine], cytokine agonists, cytokineantagonists, lung surfactants and/or antimicrobial. The compositionsaccording to the invention may also be used in combination with genereplacement therapy.

The individual components of such combinations may be administeredeither simultaneously or sequentially in a unit dosage form. The unitdosage form may be a single or multiple unit dosage forms. In anexemplary embodiment, the invention provides a combination in a singleunit dosage form. An example of a single unit dosage form is a capsulewherein both the compound of the invention and the additionaltherapeutic agent are contained within the same capsule. In an exemplaryembodiment, the invention provides a combination in a two unit dosageform. An example of a two unit dosage form is a first capsule whichcontains the compound of the invention and a second capsule whichcontains the additional therapeutic agent. Thus the term ‘single unit’or ‘two unit’ or ‘multiple unit’ refers to the object which the patientingests, not to the interior components of the object. Appropriate dosesof known therapeutic agents will be readily appreciated by those skilledin the art.

The combinations referred to herein may conveniently be presented foruse in the form of a pharmaceutical formulation. Thus, an exemplaryembodiment of the invention is a pharmaceutical formulation comprisinga) a compound of the invention; b) an additional therapeutic agent andc) a pharmaceutically acceptable excipient. In an exemplary embodiment,the pharmaceutical formulation is a unit dosage form. In an exemplaryembodiment, the pharmaceutical formulation is a single unit dosage form.In an exemplary embodiment, the pharmaceutical formulation is a two unitdosage form. In an exemplary embodiment, the pharmaceutical formulationis a two unit dosage form comprising a first unit dosage form and asecond unit dosage form, wherein the first unit dosage form includes a)a compound of the invention and b) a first pharmaceutically acceptableexcipient; and the second unit dosage form includes c) an additionaltherapeutic agent and d) a second pharmaceutically acceptable excipient.

It is to be understood that the present invention covers allcombinations of aspects and/or embodiments, as well as suitable,convenient and preferred groups described herein.

III.c) Preparation of Boron-Containing Compounds

Compounds of use in the present invention can be prepared usingcommercially available starting materials or known intermediates.Compounds of use in the present invention can be prepared usingsynthetic methods known in the art or described herein.

The following general procedures were used as indicated in generatingthe examples and can be applied, using the knowledge of one of skill inthe art, to other appropriate compounds to obtain additional analogues.

In one embodiment, the compound of the invention can be synthesizedaccording to the following scheme:

wherein R^(x) is a member selected from substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, unsubstituted cycloalkyl,substituted or unsubstituted phenylalkyl, halosubstituted alkyl andunsubstituted alkyl, wherein the acid chloride is added to a mixture of6-aminobenzo[c][1,2]oxaborol-1(3H)-ol and an agent such as Et₃N in anappropriate solvent and is stirred for an appropriate period of time atan appropriate temperature to form the product.

In one embodiment, the compound of the invention can be synthesizedaccording to the following scheme:

wherein R^(x) is a member selected from substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, unsubstituted cycloalkyl,substituted or unsubstituted phenylalkyl, halosubstituted alkyl, andunsubstituted alkyl, wherein the mixture includes a carboxylic acidcomprising molecule, a solvent such as DMF, and agents such as HATU andDIEA. The mixture can then be contacted with5-amino-2-hydroxymethylphenylboronic acid hydrochloride, and stirred foran appropriate amount of time and temperature to form the product.

Method of preparation of N-alkyl-oxaborole-6-carboxamides

In another embodiment, the compound of then invention (N.6) can besynthesized according to the following scheme:

wherein R^(y) is unsubstituted alkyl, and R^(x) is a member selectedfrom substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, unsubstituted cycloalkyl, substituted or unsubstitutedphenylalkyl, halosubstituted alkyl and unsubstituted alkyl, wherein theacid chloride is added to a mixture of6-aminobenzo[c][1,2]oxaborol-1(3H)-ol and an agent such as Et₃N in anappropriate solvent and is stirred for an appropriate period of time atan appropriate temperature to form the product. The starting material,6-alkylamino-3H-benzo[c][1,2]oxaborol-1-ol (N.5), can be synthesized bythe following scheme:

Reaction of 2-bromo-4-fluorobenzaldehyde (N.1) with anN-alkylbenzylamine in a polar aprotic solvent such asN,N-dimethylformamide in the presence of a base such as potassiumcarbonate affords the N-alkyl-N-benzyl derivative (N.2). Reaction of(N.2) with bis-pinacol diboron under the influence of a palladium (0)catalyst such as PdCl₂(dppf)₂ in a solvent such as 1,4-dioxane in thepresence of a base such as potassium acetate provides (N.3). Reductionof the aldehyde functional group of (N.3) with a reagent such as sodiumborohydride in a solvent such as ethanol, followed by hydrolysis of theboron pinacol ester under acidic conditions results in concomitant ringclosure to provide the 6-substituted oxaborole derivative (N.4).Hydrogenolysis of the N-benzyl substituent by treatment with a hydrogensource such as ammonium formate in the presence of a catalyst such aspalladium on carbon in a solvent such as ethanol affords 6-alkylamino-3H-benzo[c][1,2]oxaborol-1-ol (N.5).

Additional Methods of Synthesis

Thioether, sulfoxide and sulfone derivatives such as B, C and D can beprepared by the following reactions. Thioethers such as B can beobtained by subjecting bromide A to boronylation conditions, such astreatment with n-butyl lithium and triisopropyl borate followed byaddition of acid. Sulfoxides such as C can be obtained by subjecting Bto oxidation conditions, such as sodium periodate or one equivalent ofmCPBA. Sulfones such as D can be obtained by subjecting B to oxidationconditions such as sodium periodate over extended reaction time or twoequivalents of mCPBA.

Carbamates such as F and G can be prepared by reacting compound E withcorresponding isocyanate RNCO or ArNCO in the presence of base such astriethylamine.

Ethers such as H and I can be obtained by reacting compound E underbasic conditions with alkylbromide RBr or arylbromide ArBr.

Benzylethers such as K can be obtained by reacting compound E underbasic conditions with substituted benzyl bromide J.

Carbinol derivatives such as M can be obtained by subjecting ketone L toreducing conditions such as sodium borohydride. Ketone derivatives suchas N can be obtained by subjecting alcohol M to oxidation conditionssuch as PCC.

Amide derivatives such as P can be prepared from compound O andcorresponding anilines by standard peptide coupling conditions as shownbelow.

Amide derivatives such as S can be prepared from compound Q andcorresponding acyl chlorides by standard peptide coupling conditionssuch as shown below.

Benzylamine derivatives such as T can be obtained by reacting compound Qwith corresponding benzyl bromides under basic conditions such as shownbelow.

Sulfonamide derivatives such as U can be prepared from compound Q andcorresponding sulfonyl chlorides under basic conditions such as shownbelow.

Compounds such as W can be prepared by subjecting protected amines suchas V to acidic conditions such as shown below.

To make derivatives with a methylene linkage group such as Y, aldehyde Xcan be first subjected to reducing conditions such as sodiumborohydride, then subjected to acidic conditions such as shown below.

Compounds described herein can be converted into hydrates and solvatesby methods similar to those described herein.

IV. Methods of Inhibiting Microorganism Growth or Killing Microorganisms

The compounds of the present invention exhibit potency againstmicroorganisms, such as protozoa, and therefore have the potential tokill and/or inhibit the growth of microorganisms.

In a further aspect, the invention provides a method of killing and/orinhibiting the growth of a microorganism, said method comprising:contacting said microorganism with an effective amount of a compound ofthe invention, thereby killing and/or inhibiting the growth of themicroorganism. In an exemplary embodiment, the microorganism is aprotozoa. In an exemplary embodiment, the microorganism is akinetoplastid. In another exemplary embodiment, the protozoa is aTrypanosoma. In an exemplary embodiment, the Trypanosoma is selectedfrom the group consisting of T. avium, T. boissoni, T. brucei, T.carassii, T. cruzi, T. congolense, T. equinum, T. equiperdum, T. evansi,T. hosei, T. levisi, T. melophagium, T. parroti, T. percae, T rangeli,T. rotatorium, T. rugosae, T. sergenti, T. simiae, T. sinipercae, T.suis, T. theileri, T. triglae and T. vivax. In another exemplaryembodiment, the protozoa is a Trypanosoma brucei. In another exemplaryembodiment, the protozoa is Trypanosoma brucei brucei. In anotherexemplary embodiment, the protozoa is Trypanosoma brucei rhodesiense. Inanother exemplary embodiment, the protozoa is Trypanosoma bruceigambiense. In another exemplary embodiment, the protozoa is a member ofthe genus Leishmania. In another exemplary embodiment, the protozoa is amember of Leishmania Viannia. In an exemplary embodiment, the protozoais selected from the group consisting of L. donovani, L. infantum, L.chagasi; L. mexicana, L. amazonensis, L. venezuelensis, L. tropica, L.major, L. aethiopica, L. (V.) braziliensis, L. (V.) guyanensis, L. (V.)panamensis, and L. (V.) peruviana. In an exemplary embodiment, theprotozoa is L. donovani. In an exemplary embodiment, the protozoa is L.infantum. In another exemplary embodiment, the protozoa is a member ofthe genus Plasmodium. In another exemplary embodiment, the protozoa isselected from the group consisting of Plasmodium falciparum, Plasmodiumvivax, Plasmodium ovale, Plasmodium vivax, Plasmodium malariae andPlasmodium knowlesi. In another exemplary embodiment, the protozoa isselected from the group consisting of Plasmodium vivax, Plasmodiumovale, Plasmodium vivax and Plasmodium malariae. In another exemplaryembodiment, the protozoa is Plasmodium falciparum. In another exemplaryembodiment, the protozoa is transmitted to the animal described hereinby a mosquito infected with the protozoa. In another exemplaryembodiment, wherein the protozoa is transmitted to the animal describedherein by an Anopheles mosquito containing the protozoa. In an exemplaryembodiment, the compound is selected from the group consisting ofN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(chloro)benzamide,5-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,2-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,2-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-(trifluoromethyl)benzamide,2-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-(trifluoromethyl)benzamide,2-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)benzamide,2-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(trifluoromethyl)benzamide,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)benzamide,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(trifluoromethyl)benzamide,6-(2-chlorophenyl sulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol,6-(3-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol and6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. In anexemplary embodiment, the compound is a member selected fromN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamideand 6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. In anexemplary embodiment, the compound is6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol. In anexemplary embodiment, the compound is5-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide.In an exemplary embodiment, the compound is4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide.In an exemplary embodiment, the compound isN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide.In an exemplary embodiment, the compound is described herein, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. In anexemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or aprodrug thereof. In an exemplary embodiment, the invention provides acompound described herein, or a salt thereof. In another exemplaryembodiment, the compound of the invention is a compound describedherein, or a pharmaceutically acceptable salt thereof. In anotherexemplary embodiment, the compound is described by a formula listedherein, or a pharmaceutically acceptable salt thereof. In an exemplaryembodiment, the compound is part of a pharmaceutical formulationdescribed herein. In another exemplary embodiment, the contacting occursunder conditions which permit entry of the compound into the organism.Such conditions are known to one skilled in the art and specificconditions are set forth in the Examples appended hereto.

In another aspect, the microorganism is inside, or on the surface of ananimal. In an exemplary embodiment, the animal is selected from thegroup consisting of human, cattle, deer, reindeer, goat, honey bee, pig,sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel,yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl,pigeon, swan, and turkey. In another exemplary embodiment, the animal isa human.

In an exemplary embodiment, the microorganism is killed or its growth isinhibited through oral administration of the compound of the invention.In an exemplary embodiment, the microorganism is killed or its growth isinhibited through intravenous administration of the compound of theinvention. In an exemplary embodiment, the microorganism is killed orits growth is inhibited through topical administration of the compoundof the invention. In an exemplary embodiment, the microorganism iskilled or its growth is inhibited through intraperitoneal administrationof the compound of the invention. In an exemplary embodiment, thecompound is administered in a topically effective amount. In anexemplary embodiment, the compound is administered in a cosmeticallyeffective amount. In an exemplary embodiment, the pharmaceuticalformulation is administered in an orally effective amount.

V. Methods of Treating and/or Preventing Disease

The compounds of the present invention exhibit potency againstmicroorganisms, such as protozoa, and therefore have the potential toachieve therapeutic efficacy in the animals described herein.

In another aspect, the invention provides a method of treating and/orpreventing a disease. The method includes administering to the animal atherapeutically effective amount of the compound of the invention,sufficient to treat and/or prevent the disease. In an exemplaryembodiment, the animal is not otherwise is need of treatment with thecompound of the invention. In an exemplary embodiment, the compound ofthe invention can be used in human or veterinary medical therapy,particularly in the treatment or prophylaxis of protozoa-associateddisease. In an exemplary embodiment, the compound of the invention canbe used in human or veterinary medical therapy, particularly in thetreatment or prophylaxis of kinetoplastid-associated disease. In anexemplary embodiment, the disease is associated with a Trypanosoma. Inan exemplary embodiment, the Trypanosoma is selected from the groupconsisting of T. avium, T. boissoni, T. brucei, T carassii, T. cruzi, T.congolense, T. equinum, T. equiperdum, T evansi, T. hosei, T levisi, T.melophagium, T. parroti, T. percae, T. rangeli, T. rotatorium, T.rugosae, T. sergenti, T. simiae, T. sinipercae, T. suis, T. theileri, T.triglae and T. vivax. In an exemplary embodiment, the disease isassociated with a Trypanosoma brucei. In an exemplary embodiment, thedisease is associated with Trypanosoma brucei brucei. In an exemplaryembodiment, the disease is associated with Trypanosoma bruceirhodesiense. In an exemplary embodiment, the disease is associated withTrypanosoma brucei gambiense. In an exemplary embodiment, the disease isa typanosomiasis. In an exemplary embodiment, the disease is a humantypanosomiasis. In an exemplary embodiment, the disease is an animaltypanosomiasis. In an exemplary embodiment, the disease is selected fromthe group consisting of nagana, surra, mal de caderas, murrina decaderas, dourine, cachexial fevers, Gambian horse sickness, baleri,kaodzera, tahaga, galziekte or galzietzke and peste-boba. In anexemplary embodiment, the disease is selected from the group consistingof Chagas disease (or Human American trypanosomiasis), nagana, surra,Covering sickness (or dourine) and sleeping sickness (or Africansleeping sickness or Human African trypanosomiasis). In an exemplaryembodiment, the disease is Chagas disease. In an exemplary embodiment,the disease is sleeping sickness (or African sleeping sickness). In anexemplary embodiment, the disease is acute phase sleeping sickness. Inan exemplary embodiment, the disease is chronic phase sleeping sickness.In an exemplary embodiment, the disease is an acute phase of atypanosomiasis. In an exemplary embodiment, the disease is a chronicphase of a typanosomiasis. In an exemplary embodiment, the disease isthe non-CNS form of a typanosomiasis. In an exemplary embodiment, thedisease is the CNS form of a typanosomiasis. In an exemplary embodiment,the disease is the non-CNS form of sleeping sickness. In an exemplaryembodiment, the disease is the CNS form of sleeping sickness. In anexemplary embodiment, the disease is early stage Human Africantrypanosomiasis. In an exemplary embodiment, the disease is late stageHuman African trypanosomiasis. In another exemplary embodiment, thedisease is associated with a member of the genus Leishmania. In anotherexemplary embodiment, the disease is associated with a member ofLeishmania Viannia. In an exemplary embodiment, the disease isassociated with a member selected from the group consisting of L.donovani, L. infantum, L. chagasi; L. mexicana, L. amazonensis, L.venezuelensis, L. tropica, L. major, L. aethiopica, L. (V.)braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.)peruviana. In an exemplary embodiment, the disease is associated with L.donovani. In an exemplary embodiment, the disease is associated with L.infantum. In an exemplary embodiment, the disease is leshmaniasis. In anexemplary embodiment, the disease is a member selected from visceralleshmaniasis and/or cutaneous leshmaniasis. In an exemplary embodiment,the disease is diffuse cutaneous leshmaniasis and/or mucocutaneousleshmaniasis. In another exemplary embodiment, the disease is associatedwith a member of the genus Plasmodium. In another exemplary embodiment,the disease is associated with a member selected from the groupconsisting of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale,Plasmodium vivax, Plasmodium malariae and Plasmodium knowlesi. Inanother exemplary embodiment, the disease is associated with a memberselected from the group consisting of Plasmodium vivax, Plasmodiumovale, Plasmodium vivax and Plasmodium malariae. In another exemplaryembodiment, the disease is associated with Plasmodium falciparum. Inanother exemplary embodiment, the disease is transmitted to the animaldescribed herein by a mosquito infected with the protozoa. In anotherexemplary embodiment, the disease is transmitted to the animal describedherein by an Anopheles mosquito containing the protozoa. In anotherexemplary embodiment, the disease is malaria. In another exemplaryembodiment, the disease is cerebral malaria. In another exemplaryembodiment, the disease is chronic malaria. In an exemplary embodiment,the compound is selected from the group consisting ofN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(chloro)benzamide,5-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,2-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,2-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-(trifluoromethyl)benzamide,2-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-(trifluoromethyl)benzamide,2-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)benzamide,2-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(trifluoromethyl)benzamide,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)benzamide,N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(trifluoromethyl)benzamide,6-(2-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol,6-(3-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol and6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. In anexemplary embodiment, the compound isN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamideor 6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. In anexemplary embodiment, the compound is6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol. In anexemplary embodiment, the compound is5-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide.In an exemplary embodiment, the compound is4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide.In an exemplary embodiment, the compound isN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide.In an exemplary embodiment, the compound is described herein, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. In anexemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or aprodrug thereof. In an exemplary embodiment, the invention provides acompound described herein, or a salt thereof. In another exemplaryembodiment, the compound of the invention is a compound describedherein, or a pharmaceutically acceptable salt thereof. In anotherexemplary embodiment, the compound is described by a formula listedherein, or a pharmaceutically acceptable salt thereof. In an exemplaryembodiment, the compound is part of a pharmaceutical formulationdescribed herein. In another exemplary embodiment, the contacting occursunder conditions which permit entry of the compound into the organism.Such conditions are known to one skilled in the art and specificconditions are set forth in the Examples appended hereto.

In another exemplary embodiment, the animal is selected from the groupconsisting of human, cattle, deer, reindeer, goat, honey bee, pig,sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel,yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl,pigeon, swan, and turkey. In another exemplary embodiment, the animal isa human. In another exemplary embodiment, the animal is a mouse. Inanother exemplary embodiment, the animal is selected from the groupconsisting of a human, cattle, goat, pig, sheep, horse, cow, bull, dog,guinea pig, gerbil, rabbit, cat, chicken and turkey.

In an exemplary embodiment, the disease is treated through oraladministration of the compound of the invention. In an exemplaryembodiment, the disease is treated through intravenous administration ofthe compound of the invention. In an exemplary embodiment, the diseaseis treated through topical administration of the compound of theinvention. In an exemplary embodiment, the disease is treated throughintraperitoneal administration of the compound of the invention. In anexemplary embodiment, the compound is administered in a topicallyeffective amount. In an exemplary embodiment, the compound isadministered in a cosmetically effective amount. In an exemplaryembodiment, the pharmaceutical formulation is administered in an orallyeffective amount.

In an exemplary embodiment, the disease is associated with an infectionby a microorganism described herein. In an exemplary embodiment, thedisease is associated with an infection by a protozoa described herein.

VI. Pharmaceutical Formulations

In another aspect, the invention is a pharmaceutical formulation whichincludes: (a) a pharmaceutically acceptable excipient; and (b) acompound of the invention. In another aspect, the pharmaceuticalformulation includes: (a) a pharmaceutically acceptable excipient; and(b) a compound according to a formula described herein. In anotheraspect, the pharmaceutical formulation includes: (a) a pharmaceuticallyacceptable excipient; and (b) a compound described herein, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. Inanother aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In another aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a compound describedherein, or a salt, hydrate or solvate thereof. In another aspect, thepharmaceutical formulation includes: (a) a pharmaceutically acceptableexcipient; and (b) a salt of a compound described herein. In anexemplary embodiment, the salt is a pharmaceutically acceptable salt. Inanother aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a prodrug of a compounddescribed herein. In another aspect, the pharmaceutical formulationincludes: (a) a pharmaceutically acceptable excipient; and (b) acompound described herein. In an exemplary embodiment, thepharmaceutical formulation is a unit dosage form. In an exemplaryembodiment, the pharmaceutical formulation is a single unit dosage form.

In an exemplary embodiment, the invention is a pharmaceuticalformulation which includes: (a) a pharmaceutically acceptable excipient;and (b) a compound which is

In an exemplary embodiment, the invention is a pharmaceuticalformulation which includes: (a) a pharmaceutically acceptable excipient;and (b) a compound which is

The pharmaceutical formulations of the invention can take a variety offorms adapted to the chosen route of administration. Those skilled inthe art will recognize various synthetic methodologies that may beemployed to prepare non-toxic pharmaceutical formulations incorporatingthe compounds described herein. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable solvents thatmay be used to prepare solvates of the compounds of the invention, suchas water, ethanol, propylene glycol, mineral oil, vegetable oil anddimethylsulfoxide (DMSO).

The pharmaceutical formulation of the invention may be administeredorally, topically, intraperitoneally, parenterally, by inhalation orspray or rectally in unit dosage forms containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. It isfurther understood that the best method of administration may be acombination of methods. Oral administration in the form of a pill,capsule, elixir, syrup, lozenge, troche, or the like is particularlypreferred. The term parenteral as used herein includes subcutaneousinjections, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intrathecal injection or like injection orinfusion techniques. In an exemplary embodiment, the pharmaceuticalformulation is administered orally. In an exemplary embodiment, thepharmaceutical formulation is administered intravenously. In anexemplary embodiment, the pharmaceutical formulation is administered ina topically effective dose. In an exemplary embodiment, thepharmaceutical formulation is administered in a cosmetically effectivedose. In an exemplary embodiment, the pharmaceutical formulation isadministered in an orally effective dose.

The pharmaceutical formulations containing compounds of the inventionare preferably in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known in the art for the manufacture of pharmaceuticalformulations, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;and dispersing or wetting agents, which may be a naturally-occurringphosphatide, for example, lecithin, or condensation products of analkylene oxide with fatty acids, for example polyoxyethylene stearate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one ormore coloring agents, one or more flavoring agents, and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical formulations of the invention may also be in the form ofoil-in-water emulsions and water-in-oil emulsions. The oily phase may bea vegetable oil, for example olive oil or arachis oil, or a mineral oil,for example liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring gums, for example gum acacia or gumtragacanth; naturally-occurring phosphatides, for example soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol; anhydrides, for example sorbitan monooleate; and condensationproducts of the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents. The pharmaceutical formulations may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents, which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The composition of the invention may also be administered in the form ofsuppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Alternatively, the compositions can be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

For administration to non-human animals, the composition containing thetherapeutic compound may be added to the animal's feed or drinkingwater. Also, it will be convenient to formulate animal feed and drinkingwater products so that the animal takes in an appropriate quantity ofthe compound in its diet. It will further be convenient to present thecompound in a composition as a premix for addition to the feed ordrinking water. The composition can also added as a food or drinksupplement for humans.

Dosage levels of the order of from about 5 mg to about 250 mg perkilogram of body weight per day and more preferably from about 25 mg toabout 150 mg per kilogram of body weight per day, are useful in thetreatment of the above-indicated conditions. The amount of activeingredient that may be combined with the carrier materials to produce aunit dosage form will vary depending upon the condition being treatedand the particular mode of administration. Unit dosage forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration and rate ofexcretion, drug combination and the severity of the particular diseaseundergoing therapy.

In an exemplary embodiment, the unit dosage form contains from about 1mg to about 800 mg of a compound of the invention. In an exemplaryembodiment, the unit dosage form contains from about 1 mg to about 500mg of an active ingredient. In an exemplary embodiment, the unit dosageform contains from about 100 mg to about 800 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 200 mg to about 500 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 500 mg toabout 800 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 1 mg to about 100 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 10 mg to about 100 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 50 mg to about 100 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 25 mg toabout 75 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 40 mg to about 60 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 75 mg to about 200 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 1 mg to about 5 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 10 mg toabout 25 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 50 mg to about 350 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 200 mg to about 400 mg of a compound of theinvention.

In an exemplary embodiment, the daily dosage contains from about 1 mg toabout 800 mg of a compound of the invention. In an exemplary embodiment,the daily dosage contains from about 1 mg to about 500 mg of an activeingredient. In an exemplary embodiment, the daily dosage contains fromabout 100 mg to about 800 mg of a compound of the invention. In anexemplary embodiment, the daily dosage contains from about 200 mg toabout 500 mg of a compound of the invention. In an exemplary embodiment,the daily dosage contains from about 500 mg to about 800 mg of acompound of the invention. In an exemplary embodiment, the daily dosagecontains from about 1 mg to about 100 mg of a compound of the invention.In an exemplary embodiment, the daily dosage contains from about 10 mgto about 100 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 50 mg to about 100 mgof a compound of the invention. In an exemplary embodiment, the dailydosage contains from about 75 mg to about 200 mg of a compound of theinvention. In an exemplary embodiment, the daily dosage contains fromabout 1 mg to about 5 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 10 mg to about 25 mg ofa compound of the invention. In an exemplary embodiment, the dailydosage contains from about 50 mg to about 350 mg of a compound of theinvention. In an exemplary embodiment, the daily dosage contains fromabout 200 mg to about 400 mg of a compound of the invention.

Preferred compounds of the invention will have desirable pharmacologicalproperties that include, but are not limited to, oral bioavailability,low toxicity, low serum protein binding and desirable in vitro and invivo half-lives. Penetration of the blood brain barrier for compoundsused to treat CNS disorders is necessary, while low brain levels ofcompounds used to treat peripheral disorders are often preferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocycles may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of laboratory animalsthat receive the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcova, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lives of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

The amount of the composition required for use in treatment will varynot only with the particular compound selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will ultimately be at the discretion ofthe attendant physician or clinician.

VI. a) Testing

Preferred compounds for use in the pharmaceutical formulations describedherein will have certain pharmacological properties. Such propertiesinclude, but are not limited to, low toxicity, low serum protein bindingand desirable in vitro and in vivo half-lives. Assays may be used topredict these desirable pharmacological properties. Assays used topredict bioavailability include transport across human intestinal cellmonolayers, including Caco-2 cell monolayers. Serum protein binding maybe predicted from albumin binding assays. Such assays are described in areview by Oravcova et al. (1996, J. Chromat. B677: 1-27). Compoundhalf-life is inversely proportional to the frequency of dosage of acompound. In vitro half-lives of compounds may be predicted from assaysof microsomal half-life as described by Kuhnz and Gleschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio between LD₅₀and ED₅₀. Compounds that exhibit high therapeutic indices are preferred.The data obtained from these cell culture assays and animal studies canbe used in formulating a range of dosage for use in humans. The dosageof such compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage can vary within this range depending upon the unit dosage formemployed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition. (See, e.g.Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.1, p. 1).

VI. b) Administration

For any compound used in the method of the invention, thetherapeutically effective dose can be estimated initially from cellculture assays, as disclosed herein. For example, a dose can beformulated in animal models to achieve a circulating concentration rangethat includes the EC₅₀ (effective dose for 50% increase) as determinedin cell culture, i.e., the concentration of the test compound whichachieves a half-maximal inhibition of protozoa cell growth. Suchinformation can be used to more accurately determine useful doses inhumans.

In general, the compounds prepared by the methods, and from theintermediates, described herein will be administered in atherapeutically or cosmetically effective amount by any of the acceptedmodes of administration for agents that serve similar utilities. It willbe understood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination, the severity of the particular diseaseundergoing therapy and the judgment of the prescribing physician. Thedrug can be administered from once or twice a day, or up to 3 or 4 timesa day.

Dosage amount and interval can be adjusted individually to provideplasma levels of the active moiety that are sufficient to maintainprotozoa cell growth inhibitory effects. Usual patient dosages forsystemic administration range from 0.1 to 1000 mg/day, preferably, 1-500mg/day, more preferably 10-200 mg/day, even more preferably 100-200mg/day. Stated in terms of patient body surface areas, usual dosagesrange from 50-91 mg/m²/day.

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-10 wt %of the drug based on the total formulation, with the balance being oneor more suitable pharmaceutical excipients. Preferably, the compound ispresent at a level of about 0.1-3.0 wt %, more preferably, about 1.0 wt%.

Exemplary embodiments are summarized herein below.

In an exemplary embodiment, the invention provides a compound having astructure which is a member selected from:

wherein R* is a member selected from H and a negative charge or a saltthereof.

In an exemplary embodiment, according to the above paragraph, thecompound has a structure which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a structure according to

In an exemplary embodiment, according to any of the above paragraphs, R*is H.

In an exemplary embodiment, the invention provides a combinationcomprising the compound according to any of the above paragraphs,together with at least one other therapeutically active agent.

In an exemplary embodiment, the invention provides a pharmaceuticalcomposition comprising the compound according to any of the aboveparagraphs, and a pharmaceutically acceptable excipient.

In an exemplary embodiment, according to any of the above paragraphs,the pharmaceutical formulation is a unit dosage form.

In an exemplary embodiment, according to any of the above paragraphs,the salt of the compound according to any of the above paragraphs is apharmaceutically acceptable salt.

In an exemplary embodiment, the invention provides a method of killingand/or preventing the growth of a protozoa, comprising: contacting theprotozoa with an effective amount of the compound according to any ofthe above paragraphs, thereby killing and/or preventing the growth ofthe protozoa.

In an exemplary embodiment, according to any of the above paragraphs,the protozoa is Trypanosoma.

In an exemplary embodiment, according to any of the above paragraphs,the protozoa is Trypanosoma brucei.

In an exemplary embodiment, according to any of the above paragraphs,the Trypanosoma brucei is a member selected from Trypanosoma bruceibrucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.

In an exemplary embodiment, the invention provides a method of treatingand/or preventing a disease in an animal, comprising: administering tothe animal a therapeutically effective amount of the compound accordingto any of the above paragraphs, thereby treating and/or preventing thedisease.

In an exemplary embodiment, according to any of the above paragraphs,the disease is sleeping sickness.

In an exemplary embodiment, according to any of the above paragraphs,the animal is a human.

The invention is further illustrated by the Examples that follow. TheExamples are not intended to define or limit the scope of the invention.

EXAMPLES

The following Examples illustrate the synthesis of representativecompounds used in the present invention and the following ReferenceExamples illustrate the synthesis of intermediates in their preparation.These examples are not intended, nor are they to be construed, aslimiting the scope of the invention. It will be clear that the inventionmay be practiced otherwise than as particularly described herein.Numerous modifications and variations of the present invention arepossible in view of the teachings herein and, therefore, are within thescope of the invention.

Abbreviations: DCM/CH₂Cl₂: dichloromethane; DIEA: diisopropylethylamine;DMAP: 4-dimethylaminopyridine; DMF: N,N-dimethylformamide; EtOAc: ethylacetate; EDCI: 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide; ELS:evaporative light scattering; HATU:2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium; HOBt:N-hydroxybenzotriazole; HCO₂H: formic acid; MeOH: methanol; TEA:triethylamine; THF: tetrahydrofuran.

All temperatures are given in degrees Centigrade. Room temperature means20 to 25° C. Reagents were purchased from commercial sources or preparedfollowing standard literature procedures. Unless otherwise noted,reactions were carried out under a positive pressure of nitrogen.Reaction vessels were sealed with either rubber septa or Teflon screwcaps. Nitrogen was introduced through Tygon tubing, fitted with a largebore syringe needle. Concentration under vacuum refers to the removal ofsolvent on a Büchi Rotary Evaporator.

Analytical HPLC was performed using a Supelco discovery C₁₈ 15 cm×4.6mm/5 μm column coupled with an Agilent 1050 series VWD UV detector at210 nm. Conditions: Solvent A: H₂O/1% acetonitrile/0.1% HCO₂H; SolventB: methanol.

Proton magnetic resonance (¹H NMR) spectra were recorded on a VarianINOVA NMR spectrometer [400 MHz (¹H) or 500 MHz (¹H)]. All spectra weredetermined in the solvents indicated. Although chemical shifts arereported in ppm downfield of tetramethylsilane, they are referenced tothe residual proton peak of the respective solvent peak for ¹H NMR.Interproton coupling constants are reported in Hertz (Hz).

LCMS spectra were obtained using a ThermoFinnigan AQA MS ESI instrumentutilizing a Phenomenex Aqua 5 micron C₁₈ 125 Å 50×4.60 mm column. Thespray setting for the MS probe was at 350 μL/min with a cone voltage at25 mV and a probe temperature at 450° C. The spectra were recorded usingELS and UV (254 nm) detection. Alternatively, LCMS spectra were obtainedusing an Agilent 1200SL HPLC equipped with a 6130 mass spectrometeroperating with electrospray ionization.

Silica gel chromatography was carried out on either a Teledyne ISCOCombiFlash Companion or Companion Rf Flash Chromatography System with avariable flow rate from 5-100 mL/min. The columns used were TeledyneISCO RediSep Disposable Flash Columns (4, 12, 40, 80, or 120 g prepackedsilica gel), which were run with a maximum capacity of 1 g crude sampleper 10 g silica gel. Samples were preloaded on Celite in Analogix SampleLoading Cartridges with fits (1/in, 1/out). The eluent was 0-100% EtOAcin heptane or 0-10% MeOH in CH₂Cl₂ as a linear gradient over the lengthof the run (14-20 minutes). Peaks were detected by variable wavelengthUV absorption (200-360 nm). The resulting fractions were analyzed,combined as appropriate, and evaporated under reduced pressure toprovide purified material.

HPLC purification was performed using a 50 mm Varian Dynamax HPLC 21.4mm Microsorb Guard-8 C₁₈ column, Dyonex Chromeleon operating systemcoupled with a Varian Prostar 320 UV-vis detector (254 nm) and a Sedex55ELS detector. Conditions: Solvent A: H₂O/1% acetonitrile/0.1% HCO₂H;Solvent B: MeOH. The appropriate solvent gradient for purification wasdetermined based on the results of analytical HPLC experiments. Theresulting fractions were analyzed, combined as appropriate, andevaporated under reduced pressure to provide purified material.

The following experimental sections illustrate procedures for thepreparation of intermediates and methods for the preparation of productsaccording to this invention. It should be evident to those skilled inthe art that appropriate substitution of both the materials and methodsdisclosed herein will produce the examples illustrated below and thoseencompassed by the scope of the invention.

All solvents used were commercially available and were used withoutfurther purification. Reactions were typically run using anhydroussolvents under an inert atmosphere of N₂.

¹H, ¹³C, and ¹⁹F NMR spectra were recorded at 400 MHz for proton, 100MHz for carbon-13, and 376 MHz for fluorine-19 on a Varian 300MercuryPlus station with an Oxford AS400 Spectrometer equipped with aVarian 400 ATB PFG probe. All deuterated solvents typically contained0.03% to 0.05% v/v tetramethylsilane, which was used as the referencesignal (set at δ 0.00 for both ¹H and ¹³C).

Compounds are named using ChemDraw 7.0 or their catalogue name ifcommercially available.

Mass spectra were recorded on a Waters MS consisting of an Alliance 2795(LC) and Waters Micromass ZQ detector at 120° C. The mass spectrometerwas equipped with an electrospray ion source (ESI) operated in apositive or negative mode. The mass spectrometer was scanned betweenm/z=100-1000 with a scan time of 0.3 s.

Elemental Analysis for C, H and N composition was performed using aCostech Instrument Elemental Combustion System ECS4010 with a heliumflow of 100 mL/min (14 psi), oxygen 20 mL/min (10 psi), air 25 psi andpurge of 50 mL/min. The reported analyses are an average of two runs.

HPLC analyses were performed on a Water 600 Controller system with aWaters 717 Plus Autosampler and a Waters 2996 Photodiode Array Detector.The column used was an ACE C₁₈, 5 μm, 4.6×150 mm. A linear gradient wasapplied, starting at 95% A (A: 0.1% H₃PO₄ in water) and ending at 90% B(B: MeCN) over 6 min and then maintained at 90% B until the 10 min mark.The column was then re-equilibrated over 3 min to 95:5 with a total runtime of 20 min. The column temperature was at rt with the flow rate of1.0 mL/min. The Diode Array Detector was scanned from 200-400 nm. Forhigh purity samples requiring baseline subtraction, a linear gradientwas applied, starting at 99% A (A: 0.1% H₃PO₄ in water) and ending at90% B (B: MeCN) over 15 min. The column was then re-equilibrated over 3min to 99% A with a total run time of 23 min. The column temperature wasat rt with the flow rate of 1.0 mL/min. The Diode Array Detector wasscanned from 200-400 nm. A blank MeOH sample was run immediately priorto the sample of which purity was to be determined: this was thensubtracted to obtain the baseline subtracted chromatogram.

Thin layer chromatography (TLC) was performed on Alugram® (Silica gel 60F₂₅₄) from Mancherey-Nagel and UV was typically used to visualize thespots. Additional visualization methods were also employed in somecases. In these cases the TLC plate was developed with iodine (generatedby adding approximately 1 g of I₂ to 10 g silica gel and thoroughlymixing), vanillin (generated by dissolving about 1 g vanillin in 100 mL10% H₂SO₄), potassium permanganate (generated by dissolving 1.5 g KMnO₄and 10 g K₂CO₃ in 1.25 mL NaOH and 200 mL H₂O), ninhydrin (availablecommercially from Aldrich), or Magic Stain (generated by thoroughlymixing 25 g (NH₄)₆Mo₇O₂₄.4H₂O, 5 g (NH₄)₂Ce(IV)(NO₃)₆ in 450 mL H₂O and50 mL conc H₂SO₄) to visualize the compound. Flash chromatography waspreformed using typically 40-63 μm (230-400 mesh) silica gel fromSilicycle following analogous techniques to those disclosed by Still etal. Typical solvents used for flash chromatography or thin layerchromatography (TLC) were mixtures of CHCl₃/MeOH, CH₂Cl₂/MeOH,EtOAc/MeOH and hexane/EtOAc. Reverse phase flash chromatography wereperformed on a Biotage® using a Biotage C₁₈ cartridges and a H₂O/MeOHgradient (typically eluting from 5% MeOH/H₂O to 90% MeOH/H₂O).

Preparative chromatography was performed on either a Waters Prep LC 4000System using a Waters 2487 Diode Array or on a Waters LC Module 1 plus.The column used were either a Waters×Terra Prep C₁₈, 5 μm, 30×100 mm,Phenomenex Luna C₁₈, 5 μm, 21.6×250 mm, or a Phenomenex Gemini C₁₈, 5μm, 100×30 mm. Narrow gradients with MeCN/H₂O (water containing either0.1% TFA, 0.1% AcOH, 0.1% HCO₂H or 0.1% NH₄OAc) were used to elute thecompound at a flow rate of approximately 20 mL/min and a total run timebetween 20-30 min.

Starting materials used were either available from commercial sources orprepared according to literature procedures and had experimental data inaccordance with those reported. 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol,for example, can be synthesized according to the methods described inU.S. Pat. Pubs. US20060234981 and US20070155699.

Example 1N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide(H1)

To a mixture of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (50.0 mg, 0.335mmol) and Et₃N (50.9 mg, 0.503 mmol) in dry CH₂Cl₂ (5 mL) was added2-(trifluoromethyl)benzoyl chloride (69.9 mg, 0.335 mmol) dropwise at 0°C., followed by stirring at room temperature overnight. Then theprecipitate was collected by filtration and washed with CH₂Cl₂ to affordthe title compound as pale yellow solid in 61% yield. ¹H NMR (DMSO-d₆,300 MHz): δ 10.56 (s, 1H), 9.24 (s, 1H), 8.13 (d, J=1.8 Hz, 1H),7.85-7.63 (m, 5H), 7.36 (d, J=8.1 Hz, 1H), 4.95 (s, 2H). Purity: 100% at220 nm and 100% at 254 nm. MS: m/z=322 (M+1, ESI+).

N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)benzamide(H2)

This compound is produced by the similar method as H1 by substituting2-(trifluoromethyl)benzoyl chloride with 3-(trifluoromethyl)benzoylchloride.

¹H NMR (DMSO-d₆, 400 MHz): δ 10.51 (s, 1H), 9.24 (s, 1H), 8.24-8.35 (m,2H), 8.17 (d, J=1.8 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.72-7.84 (m, 2H),7.41 (d, J=8.2 Hz, 1H), 4.98 (s, 2H). Purity: 94.1% at 220 nm and 93.4%at 254 nm. MS: m/z=322 (M+1, ESI+).

N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(trifluoromethyl)benzamide(H3)

This compound is produced by the similar method as H1 by substituting2-(trifluoromethyl)benzoyl chloride with 4-(trifluoromethyl)benzoylchloride.

¹H NMR (DMSO-d₆, 400 MHz): δ 10.51 (s, 1H), 9.24 (s, 1H), 8.09-8.20 (m,3H), 7.92 (d, J=8.4 Hz, 1H), 7.77 (dd, J=8.2 & 2.0 Hz, 1H), 7.41 (d,J=8.4 Hz, 1H), 4.98 (s, 2H). Purity: 94.1% at 220 nm and 94.4% at 254nm. MS: m/z=322 (M+1, ESI+).

2-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H4)

H4 was prepared using a procedure similar to that of H17 by substituting5-fluoro-2-(trifluoromethyl)benzoyl chloride with 2-fluorobenzoylchloride. LCMS (m/z): 272 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.97(s, 2H) 7.30-7.42 (m, 3H) 7.54-7.62 (m, 1H) 7.63-7.75 (m, 2H) 8.15 (s,1H) 9.24 (s, 1H) 10.43 (s, 1H).

3-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H5)

H5 was prepared using a procedure similar to that of H17 by substituting5-fluoro-2-(trifluoromethyl)benzoyl chloride with 3-fluorobenzoylchloride. LCMS (m/z): 272 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.97(s, 2H) 7.35-7.52 (m, 2H) 7.60 (td, J=8.0, 5.9 Hz, 1H) 7.71-7.88 (m, 3H)8.17 (d, J=2.0 Hz, 1H) 9.24 (s, 1H) 10.35 (s, 1H).

4-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H6)

A 40 mL scintillation vial containing a mixture of 4-fluorobenzoic acid(275 mg 1.96 mmol, 1.1 eq), DMF (15 mL), HATU (710 mg, 1.9 mmol, 1.05eq) and DIEA (460 μl, 2.7 mmol, 1.5 eq) was allowed to stir at roomtemperature for 2 hours. 5-amino-2-hydroxymethylphenylboronic acidhydrochloride (330 mg, 1.78 mmol, 1 eq) was then added in one portion.The reaction stirred at room temperature overnight. The solvent wasremoved under vacuum and the resulting oil was purified by silica gelchromatography to furnish H6. LCMS (m/z) 272 (M+H); ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.97 (s, 2H) 7.32-7.44 (m, 3H) 7.76 (dd, J=8.2, 2.1 Hz,1H) 8.05 (dd, J=8.8, 5.5 Hz, 2H) 8.16 (t, J=2.0 Hz, 1H) 9.22 (s, 1H)10.30 (s, 1H).

2-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H7)

H7 was prepared using a procedure similar to that of H17 by substituting5-fluoro-2-(trifluoromethyl)benzoyl chloride with 2-chlorobenzoylchloride. LCMS (m/z): 288 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.97(s, 2H) 7.39 (d, J=8.2 Hz, 1H) 7.45-7.55 (m, 2H) 7.55-7.62 (m, 2H) 7.71(dd, J=8.3, 2.1 Hz, 1H) 8.17 (d, J=1.8 Hz, 1H) 9.25 (s, 1H) 10.53 (s,1H).

3-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H8)

H8 was prepared using a procedure similar to that of H17 by substituting5-fluoro-2-(trifluoromethyl)benzoyl chloride with 3-chlorobenzoylchloride. LCMS (m/z): 288 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.97(s, 2H) 7.40 (d, J=8.6 Hz, 1H) 7.58 (t, J=7.8 Hz, 1H) 7.63-7.70 (m, 1H)7.76 (dd, J=8.3, 2.0 Hz, 1H) 7.93 (ddd, J=8.0, 1.4, 1.2 Hz, 1H) 8.02 (t,J=1.9 Hz, 1H) 8.17 (d, J=1.8 Hz, 1H) 9.23 (s, 1H) 10.39 (s, 1H).

4-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H9)

H9 was produced by a similar method as H63 by substitutingthiophene-2-carbonyl chloride with 4-chlorobenzoyl chloride.

3-Bromo-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H10)

H10 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-bromobenzoyl chloride. LCMS (m/z): 332 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 4.98 (s, 2H) 7.40 (d, J=8.2 Hz, 1H) 7.51 (t, J=7.8 Hz,1H) 7.76 (dd, J=8.2, 2.1 Hz, 1H) 7.80 (ddd, J=8.0, 2.0, 1.0 Hz, 1H) 7.97(ddd, J=8.0, 1.4, 1.2 Hz, 1H) 8.16 (ddd, J=3.5, 2.0, 1.8 Hz, 2H) 9.24(s, 1H) 10.39 (s, 1H).

3,4-Dichloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H11)

H11 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3,4-dichlorobenzoyl chloride. LCMS (m/z): 322 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 4.97 (s, 2H) 7.40 (d, J=8.4 Hz, 1H) 7.75 (dd, J=8.3, 1.9Hz, 1H) 7.83 (d, J=8.4 Hz, 1H) 7.95 (dd, J=8.3, 2.1 Hz, 1H) 8.16 (d,J=1.4 Hz, 1H) 8.23 (d, J=2.0 Hz, 1H) 9.24 (s, 1H) 10.43 (s, 1H).

3-Chloro-2-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H12)

H12 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-chloro-2-fluorobenzoyl chloride. LCMS (m/z): 306 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.33-7.43 (m, 2H) 7.65 (ddd, J=7.8,6.2, 1.7 Hz, 1H) 7.71 (dd, J=8.2, 2.0 Hz, 1H) 7.74-7.80 (m, 1H) 8.14 (d,J=1.8 Hz, 1H) 9.26 (s, 1H) 10.58 (s, 1H).

5-Chloro-2-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H13)

H13 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-chloro-6-fluorobenzoyl chloride. LCMS (m/z): 306 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.30-7.48 (m, 2H) 7.64 (ddd, J=8.8,4.3, 2.8 Hz, 1H) 7.71 (dd, J=8.2, 2.0 Hz, 1H) 7.75 (dd, J=5.9, 2.7 Hz,1H) 8.14 (d, J=1.8 Hz, 1H) 9.26 (s, 1H) 10.54 (s, 1H).

2-Chloro-4-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H14)

H14 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-chloro-4-fluorobenzoyl chloride. LCMS (m/z): 306 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 4.96 (s, 2H) 7.30-7.41 (m, 2H) 7.59 (dd, J=9.1, 2.4Hz, 1H) 7.64-7.74 (m, 2H) 8.15 (d, J=2.0 Hz, 1H) 9.25 (s, 1H) 10.53 (s,1H).

2,4-Difluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H15)

H15 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2,4-difluorobenzoyl chloride. LCMS (m/z): 290 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 4.97 (s, 2H) 7.16-7.30 (m, 1H) 7.31-7.50 (m, 2H)7.65-7.83 (m, 2H) 8.13 (s, 1H) 9.24 (s, 1H) 10.43 (s, 1H).

2,6-Difluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H16)

H16 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2,6-difluorobenzoyl chloride. LCMS (m/z): 290 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 4.97 (s, 2H) 7.15-7.32 (m, 2H) 7.40 (d, J=8.4 Hz, 1H)7.59 (tt, J=8.5, 6.6 Hz, 1H) 7.68 (dd, J=8.2, 2.1 Hz, 1H) 8.14 (d, J=1.8Hz, 1H) 10.81 (s, 1H).

5-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide(H17)

A 500 mL round bottom flask was charged with a mixture of5-amino-2-hydroxymethylphenylboronic acid hydrochloride (2 g, 10.8 mmol,1 eq), triethylamine (4.5 mL, 32.4 mmol, 3 eq) and dichloromethane (200mL). 5-fluoro-2-(trifluoromethyl)benzoyl chloride (1.7 mL, 11.4 mmol,1.05 eq) was then added and the reaction mixture was allowed to stair atroom temperature overnight. Aqueous hydrochloric acid (1 M, 100 mL) wasadded to the mixture, and the reaction was stirred for an additionalhour. The resulting precipitate was collected, and the resultantoff-white powder was dried under vacuum.

LCMS (m/z) 340 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.97 (s, 2H) 7.39(d, J=8.4 Hz, 1H) 7.57 (td, J=8.7, 2.6 Hz, 1H) 7.65 (dd, J=8.3, 2.1 Hz,1H) 7.71 (dd, J=8.7, 2.6 Hz, 1H) 7.94 (dd, J=8.8, 5.3 Hz, 1H) 8.13 (d,J=2.0 Hz, 1H) 9.26 (s, 1H) 10.63 (s, 1H). Amount Obtained: 2.44 g, 67%yield.

2-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-6-trifluoromethyl-benzamide(H18)

H18 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-fluoro-6-(trifluoromethyl)benzoyl chloride. LCMS (m/z): 340 (M+H); ¹HNMR (400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.40 (d, J=8.2 Hz, 1H) 7.63(dd, J=8.2, 2.0 Hz, 1H) 7.67-7.85 (m, 3H) 8.12 (d, J=2.0 Hz, 1H) 9.26(s, 1H) 10.81 (s, 1H).

4-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide(H19)

H19 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-fluoro-2-(trifluoromethyl)-benzoyl chloride. LCMS (m/z): 339 (M+H); ¹HNMR (400 MHz, DMSO-d6) δ ppm 4.96 (s, 2H) 7.39 (d, J=8.2 Hz, 1H)7.61-7.73 (m, 2H) 7.74-7.89 (m, 2H) 8.13 (d, J=1.6 Hz, 1H) 9.25 (s, 1H)10.59 (s, 1H).

2-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-trifluoromethyl-benzamide(H20)

H20 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-fluoro-3-(trifluoromethyl)benzoyl chloride. LCMS (m/z): 362 (M+Na); ¹HNMR (400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.41 (d, J=8.4 Hz, 1H) 7.55(t, J=7.8 Hz, 1H) 7.71 (dd, J=8.2, 2.0 Hz, 1H) 7.89-8.07 (m, 2H) 8.15(d, J=2.0 Hz, 1H) 9.26 (s, 1H) 10.66 (s, 1H).

2-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-trifluoromethyl-benzamide(H21)

H21 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-fluoro-4-(trifluoromethyl)benzoyl chloride. LCMS (m/z): 362 (M+Na); ¹HNMR (400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.41 (d, J=8.6 Hz, 1H)7.67-7.80 (m, 2H) 7.83-7.98 (m, 2H) 8.14 (d, J=1.8 Hz, 1H) 9.26 (s, 1H)10.64 (s, 1H).

2-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-5-trifluoromethyl-benzamide(H22)

H22 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-fluoro-5-(trifluoromethyl)benzoyl chloride. LCMS (m/z): 340 (M+H); ¹HNMR (400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.41 (d, J=8.4 Hz, 1H) 7.63(t, J=9.1 Hz, 1H) 7.72 (dd, J=8.2, 2.0 Hz, 1H) 7.93-8.03 (m, 1H) 8.07(dd, J=6.2, 2.3 Hz, 1H) 8.14 (d, J=2.0 Hz, 1H) 9.26 (s, 1H) 10.62 (s,1H).

2-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-5-trifluoromethyl-benzamide(H23)

H23 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-chloro-5-(trifluoromethyl)benzoyl chloride. LCMS (m/z): 356 (M+H); ¹HNMR (400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.40 (d, J=8.4 Hz, 1H) 7.70(dd, J=8.2, 2.0 Hz, 1H) 7.76-7.94 (m, 2H) 8.04 (d, J=2.3 Hz, 1H) 8.16(d, J=1.8 Hz, 1H) 9.26 (s, 1H) 10.66 (s, 1H).

3-Chloro-2-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-6-trifluoromethyl-benzamide(H24)

H24 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-chloro-2-fluoro-6-(trifluoromethyl)benzoyl chloride. LCMS (m/z): 374(M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.41 (d, J=8.2 Hz,1H) 7.61 (dd, J=8.3, 2.0 Hz, 1H) 7.77 (d, J=8.8 Hz, 1H) 7.98 (t, J=7.6Hz, 1H) 8.10 (d, J=1.8 Hz, 1H) 9.27 (s, 1H) 10.89 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,4-bis-trifluoromethyl-benzamide(H25)

H25 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2,4-bis(trifluoromethyl)benzoyl chloride. LCMS (m/z): 412 (M+Na); ¹H NMR(400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.41 (d, J=8.4 Hz, 1H) 7.66 (dd,J=8.2, 2.0 Hz, 1H) 8.00 (d, J=8.0 Hz, 1H) 8.13 (d, J=1.8 Hz, 1H)8.18-8.27 (m, 2H) 9.27 (s, 1H) 10.71 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,5-bis-trifluoromethyl-benzamide(H26)

H26 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2,5-bis(trifluoromethyl)benzoyl chloride. LCMS (m/z): 390 (M+H); ¹H NMR(400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.40 (d, J=8.4 Hz, 1H) 7.66 (dd,J=8.2, 2.0 Hz, 1H) 8.11 (s, 2H) 8.13 (d, J=1.8 Hz, 1H) 8.19 (s, 1H) 9.26(s, 1H) 10.71 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3,5-bis-trifluoromethyl-benzamide(H27)

H27 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2,5-bis(trifluoromethyl)benzoyl chloride. LCMS (m/z): 390 (M+H); ¹H NMR(400 MHz, DMSO-d6) δ ppm 4.99 (s, 2H) 7.44 (d, J=8.2 Hz, 1H) 7.78 (dd,J=8.2, 2.0 Hz, 1H) 8.16 (d, J=1.8 Hz, 1H) 8.38 (s, 1H) 8.62 (s, 2H) 9.26(br. s., 1H) 10.71 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-methyl-benzamide(H28)

H28 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-methylbenzoyl chloride. LCMS (m/z): 268 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 2.39 (s, 3H) 4.96 (s, 2H) 7.26-7.34 (m, 2H) 7.34-7.42 (m,2H) 7.46 (d, J=7.6 Hz, 1H) 7.72 (dd, J=8.2, 1.8 Hz, 1H) 8.19 (d, J=1.2Hz, 1H) 9.22 (s, 1H) 10.32 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methyl-benzamide(H29)

H29 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-methylbenzoyl chloride. LCMS (m/z): 268 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 2.38 (s, 3H) 4.94 (s, 2H) 7.34-7.42 (m, 3H) 7.69-7.78 (m,3H) 8.14 (s, 1H) 9.19 (s, 1H) 10.21 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methyl-benzamide(H30)

H30 was produced by a similar method as H63 by substitutingthiophene-2-carbonyl chloride with 4-methylbenzoyl chloride.

4-Ethyl-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H31)

H31 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with 4-ethylbenzoyl chloride. LCMS (m/z): 282 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm1.22 (t, J=7.6 Hz, 3H) 2.69 (q, J=7.6 Hz, 2H) 4.97 (s, 2H) 7.33-7.42 (m,3H) 7.76 (dd, J=8.3, 2.1 Hz, 1H) 7.86-7.94 (m, 2H) 8.17 (d, J=1.8 Hz,1H) 9.21 (s, 1H) 10.20 (s, 1H).

4-Butyl-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H32)

H32 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-n-butylbenzoyl chloride. LCMS (m/z): 310 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 0.83-0.97 (m, 3H) 1.32 (dq, J=14.9, 7.4 Hz, 2H) 1.52-1.67(m, 2H) 2.66 (t, J=7.6 Hz, 2H) 4.97 (s, 2H) 7.30-7.43 (m, 3H) 7.76 (dd,J=8.3, 2.1 Hz, 1H) 7.84-7.93 (m, 2H) 8.17 (d, J=1.8 Hz, 1H) 9.21 (s, 1H)10.20 (s, 1H).

4-tert-Butyl-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H33)

H33 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-(trifluoromethyl)benzoyl chloride. LCMS (m/z): 310 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 4.97 (s, 2H) 7.38 (d, J=8.4 Hz, 1H)7.50-7.59 (m, 2H) 7.76 (dd, J=8.2, 2.0 Hz, 1H) 7.85-7.95 (m, 2H) 8.16(d, J=1.8 Hz, 1H) 9.21 (s, 1H) 10.21 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3,5-dimethyl-benzamide(H34)

H34 was produced by a similar method as H75 by substitutingpyrazine-2-carboxylic acid with 3,5-dimethylbenzoic acid.

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-methoxy-benzamide(H35)

H35 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-methoxybenzoyl chloride. LCMS (m/z): 284 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 3.91 (s, 3H) 4.96 (s, 2H) 7.02-7.11 (m, 1H) 7.18 (d,J=8.4 Hz, 1H) 7.37 (d, J=8.2 Hz, 1H) 7.46-7.54 (m, 1H) 7.65 (dd, J=7.6,1.8 Hz, 1H) 7.74 (dd, J=8.2, 2.0 Hz, 1H) 8.16 (d, J=1.8 Hz, 1H) 9.22 (s,1H) 10.14 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methoxy-benzamide(H36)

H36 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-methoxybenzoyl chloride. LCMS (m/z): 284 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 3.84 (s, 3H) 4.97 (s, 2H) 7.12-7.19 (m, 1H) 7.35-7.59 (m,4H) 7.77 (dd, J=8.3, 2.0 Hz, 1H) 8.15 (d, J=1.8 Hz, 1H) 9.22 (s, 1H)10.25 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-benzamide(H37)

H37 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-methoxybenzoyl chloride. LCMS (m/z): 284 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 3.84 (s, 3H) 4.96 (s, 2H) 6.96-7.12 (m, 2H) 7.37 (d,J=8.6 Hz, 1H) 7.76 (dd, J=8.3, 2.0 Hz, 1H) 7.91-8.03 (m, 2H) 8.15 (d,J=2.0 Hz, 1H) 9.20 (s, 1H) 10.12 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,4-ditnethoxy-benzamide(H38)

H38 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3,5-dimethoxybenzoyl chloride. LCMS (m/z): 314 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 3.85 (s, 3H) 3.96 (s, 3H) 4.96 (s, 2H) 6.67 (dd, J=8.6,2.3 Hz, 1H) 6.71 (d, J=2.3 Hz, 1H) 7.36 (d, J=8.4 Hz, 1H) 7.74 (dd,J=8.1, 1.9 Hz, 1H) 7.77 (d, J=8.6 Hz, 1H) 8.13 (d, J=1.8 Hz, 1H) 9.20(br. s., 1H) 9.95 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3,4-ditnethoxy-benzamide(H39)

H39 was produced by a similar method as H75 by substitutingpyrazine-2-carboxylic acid with 3,4-dimethoxybenzoic acid.

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,6-dimethoxy-benzamide(H40)

H40 was produced by a similar method as H63 by substitutingthiophene-2-carbonyl chloride with 2,6-dimethoxybenzoyl chloride.

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,4,6-trimethoxy-benzamide(H41)

H41 was produced by a similar method as H63 by substitutingthiophene-2-carbonyl chloride with 3,4,5-trimethoxybenzoyl chloride.

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-isopropoxy-benzamide(H42)

H42 was prepared using a procedure similar to that of H6 by substituting4-fluorobenzoic acid with 4-isopropoxybenzoic acid. LCMS (m/z): 312(M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.1 Hz, 7H) 4.74 (spt,J=6.0 Hz, 1H) 4.96 (s, 2H) 6.98-7.09 (m, 2H) 7.37 (d, J=8.2 Hz, 1H) 7.75(dd, J=8.2, 2.0 Hz, 1H) 7.90-7.98 (m, 2H) 8.15 (d, J=1.6 Hz, 1H) 9.23(br. s., 1H) 10.11 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-3-methyl-benzamide(H43)

H43 was prepared using a procedure similar to that of H6 by substituting4-fluorobenzoic acid with 4-methoxy-3-methylbenzoic acid. LCMS (m/z):298 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.22 (s, 3H) 3.87 (s, 3H)4.96 (s, 2H) 7.06 (d, J=8.6 Hz, 1H) 7.37 (d, J=8.2 Hz, 1H) 7.75 (dd,J=8.3, 1.9 Hz, 1H) 7.81 (d, J=1.8 Hz, 1H) 7.86 (dd, J=8.5, 2.2 Hz, 1H)8.14 (d, J=1.6 Hz, 1H) 10.09 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethoxy-benzamide(H44)

H44 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-(trifluoromethoxy)benzoyl chloride. LCMS (m/z): 338 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 4.96 (s, 2H) 7.38 (d, J=8.2 Hz, 1H) 7.47-7.60 (m,2H) 7.60-7.77 (m, 4H) 8.15 (d, J=1.8 Hz, 1H) 9.25 (s, 1H) 10.51 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-trifluoromethoxy-benzamide(H45)

H45 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-(trifluoromethoxy)benzoyl chloride. LCMS (m/z): 338 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 4.98 (s, 2H) 7.41 (d, J=8.4 Hz, 1H) 7.58-7.66 (m,1H) 7.69 (t, J=8.0 Hz, 1H) 7.76 (dd, J=8.2, 2.0 Hz, 1H) 7.93 (s, 1H)8.03 (dt, J=7.8, 1.3 Hz, 1H) 8.15 (d, J=2.0 Hz, 1H) 9.24 (s, 1H) 10.43(s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-trifluoromethoxy-benzamide(H46)

H46 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-(trifluoromethoxy)benzoyl chloride. LCMS (m/z): 338 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.40 (d, J=8.2 Hz, 1H) 7.54 (d, J=8.0Hz, 2H) 7.76 (dd, J=8.2, 2.0 Hz, 1H) 8.05-8.13 (m, 2H) 8.16 (d, J=1.8Hz, 1H) 9.24 (s, 1H) 10.39 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-trifluoromethylsulfanyl-benzamide(H47)

H47 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-(trifluoromethylsulfanyl)benzoyl chloride. LCMS (m/z): 354 (M+H); ¹HNMR (400 MHz, DMSO-d6) δ ppm 4.98 (s, 2H) 7.41 (d, J=8.2 Hz, 1H) 7.77(dd, J=8.3, 2.0 Hz, 1H) 7.89 (d, J=8.2 Hz, 2H) 8.03-8.13 (m, 2H) 8.18(d, J=2.0 Hz, 1H) 9.25 (s, 1H) 10.48 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-nitro-benzamide(H48)

H48 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-nitrobenzoyl chloride. LCMS (m/z): 299 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 4.97 (s, 2H) 7.40 (d, J=8.8 Hz, 1H) 7.66 (dd, J=8.3, 2.1Hz, 1H) 7.72-7.82 (m, 2H) 7.84-7.92 (m, 1H) 8.09-8.20 (m, 2H) 9.26 (s,1H) 10.69 (s, 1H).

4-Cyano-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H49)

H49 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-cyanobenzoyl chloride. LCMS (m/z): 279 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 4.98 (s, 2H) 7.41 (d, J=8.2 Hz, 1H) 7.77 (dd, J=8.2, 2.0Hz, 1H) 7.99-8.08 (m, 2H) 8.08-8.16 (m, 2H) 8.18 (d, J=1.8 Hz, 1H) 9.25(s, 1H) 10.53 (s, 1H).

4-Dimethylamino-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H50)

H50 was produced by a similar method as H63 by substitutingthiophene-2-carbonyl chloride with 4-(dimethylamino)benzoyl chloride.

4-Acetylamino-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H51)

H51 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-(N-acetylamino)benzoyl chloride. LCMS (m/z): 311 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 2.09 (s, 3H) 4.96 (s, 2H) 7.37 (d, J=8.2 Hz, 1H)7.65-7.81 (m, 3H) 7.89-8.00 (m, 2H) 8.15 (d, J=2.0 Hz, 1H) 9.21 (s, 1H)10.15 (s, 1H) 10.22 (s, 1H).

4-{[1-Dimethylamino-meth-(E)-ylidene]-sulfamoyl}-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H52)

H52 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with thedimethylformamide complex of 4-(sulfamido)benozyl chloride. LCMS (m/z):388 (M+H); ¹H NMR (400 MHz, Acetone-d6) δ ppm 3.02 (s, 3H) 3.26 (s, 3H)5.01 (s, 2H) 7.41 (d, J=8.2 Hz, 1H) 7.85 (dt, J=8.3, 1.8 Hz, 1H)7.89-7.97 (m, 2H) 8.08-8.14 (m, 3H) 8.21 (s, 1H) 8.25 (t, J=2.1 Hz, 1H)9.79 (br. s., 1H).

4-Phenyl-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H53)

This compound was produced by a similar method as H75 by substitutingpyrazine-2-carboxylic acid with biphenyl-4-carboxylic acid.

Naphthalene-1-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H54)

H54 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with1-naphthoyl chloride. LCMS (m/z) δ 304 (M+H); ¹H NMR (400 MHz, DMSO-d6)δ ppm 4.99 (s, 2H) 7.41 (d, J=8.2 Hz, 1H) 7.56-7.66 (m, 3H) 7.72-7.85(m, 2H) 8.00-8.06 (m, 1H) 8.08 (d, J=8.4 Hz, 1H) 8.15-8.22 (m, 1H) 8.26(d, J=1.8 Hz, 1H) 9.25 (s, 1H) 10.60 (s, 1H).

Naphthalene-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H55)

H55 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-naphthoyl chloride. LCMS (m/z): 304 (M+H); ¹H NMR (400 MHz, DMSO-d6) δppm 4.99 (s, 2H) 7.41 (d, J=8.0 Hz, 1H) 7.58-7.69 (m, 2H) 7.82 (dd,J=8.3, 2.1 Hz, 1H) 7.99-8.13 (m, 4H) 8.23 (d, J=1.8 Hz, 1H) 8.60 (s, 1H)9.24 (s, 1H) 10.47 (s, 1H).

Benzo[1,3]dioxole-5-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H56)

H56 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withpiperonyloyl chloride. LCMS (m/z): 298 (M+H); ¹H NMR (400 MHz, DMSO-d6)δ ppm 4.96 (s, 2H) 6.13 (s, 2H) 7.06 (d, J=8.2 Hz, 1H) 7.37 (d, J=8.4Hz, 1H) 7.53 (d, J=1.8 Hz, 1H) 7.59 (dd, J=8.2, 1.8 Hz, 1H) 7.74 (dd,J=8.2, 2.1 Hz, 1H) 8.14 (d, J=1.8 Hz, 1H) 9.21 (s, 1H).

Cyclopropanecarboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H57)

H57 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withcyclopropanecarbonyl chloride. LCMS (m/z): 218 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 0.73-0.86 (m, 4H) 1.71-1.88 (m, 1H) 4.93 (s, 2H) 7.31 (d,J=8.2 Hz, 1H) 7.62 (dd, J=8.2, 2.0 Hz, 1H) 7.97 (d, J=1.8 Hz, 1H) 9.17(s, 1H) 10.19 (s, 1H).

Cyclohexanecarboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H58)

H58 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withcyclohexanecarbonyl chloride. LCMS (m/z): 260 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.09-1.35 (m, 3H) 1.34-1.50 (m, 2H) 1.65 (d, J=12.5 Hz,1H) 1.78 (t, J=14.3 Hz, 4H) 2.27-2.40 (m, 1H) 4.92 (s, 2H) 7.30 (d,J=8.4 Hz, 1H) 7.61 (dd, J=8.2, 2.0 Hz, 1H) 8.00 (d, J=2.0 Hz, 1H) 9.16(s, 1H) 9.80 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-nicotinamide (H59)

H59 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withnicotinoyl chloride hydrochloride. LCMS (m/z): 255 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 4.98 (s, 2H) 7.41 (d, J=8.2 Hz, 1H) 7.58 (ddd,J=8.0, 4.8, 0.9 Hz, 1H) 7.77 (dd, J=8.2, 2.0 Hz, 1H) 8.17 (d, J=1.8 Hz,1H) 8.31 (dt, J=7.9, 2.0 Hz, 1H) 8.76 (dd, J=4.8, 1.7 Hz, 1H) 9.07-9.15(m, 1H) 9.24 (s, 1H) 10.48 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-isonicotinamide(H60)

H60 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withisonicotinoyl chloride hydrochloride. LCMS (m/z): 256 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 4.98 (s, 2H) 7.41 (d, J=8.2 Hz, 1H) 7.74-7.83 (m,1H) 7.89 (d, J=5.9 Hz, 2H) 8.18 (d, J=1.8 Hz, 1H) 8.79 (d, J=6.1 Hz, 2H)9.26 (s, 1H) 10.58 (br. s., 1H).

Furan-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H61)

H61 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with 2-furoylchloride. LCMS (m/z): 244 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.96(s, 2H) 6.70 (dd, J=3.4, 1.7 Hz, 1H) 7.34 (dd, J=3.5, 0.8 Hz, 1H) 7.37(d, J=8.2 Hz, 1H) 7.74 (dd, J=8.3, 2.1 Hz, 1H) 7.93 (dd, J=1.8, 0.8 Hz,1H) 8.13 (d, J=1.8 Hz, 1H) 9.22 (s, 1H) 10.20 (s, 1H).

3-Methyl-furan-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H62)

H62 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-methylfuran-2-carbonyl chloride. LCMS (m/z): 258 (M+H); ¹H NMR (400MHz, DMSO-d6) δ ppm 2.35 (s, 3H) 4.95 (s, 2H) 6.59 (d, J=1.8 Hz, 1H)7.35 (d, J=8.2 Hz, 1H) 7.73 (dd, J=8.3, 2.1 Hz, 1H) 7.78 (d, J=1.8 Hz,1H) 8.18 (d, J=2.0 Hz, 1H) 9.19 (s, 1H) 10.06 (s, 1H).

Thiophene-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H63)

To a suspension of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (50.0 mg, 0.335mmol) and Et₃N (50.9 mg, 0.503 mmol) in dry CH₂Cl₂ (5 mL) was addedthiophene-2-carbonyl chloride (49.1 mg, 0.335 mmol) dropwise at 0° C.,followed by stirring at room temperature overnight. Then the precipitatewas collected by filtration and washed with CH₂Cl₂ to afford H63.

LCMS (m/z): 260 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H) 7.23(dd, J=4.9, 3.7 Hz, 1H) 7.39 (d, J=8.2 Hz, 1H) 7.73 (dd, J=8.3, 2.0 Hz,1H) 7.85 (dd, J=5.1, 1.0 Hz, 1H) 8.03 (dd, J=3.8, 1.1 Hz, 1H) 8.09 (d,J=2.0 Hz, 1H) 9.22 (s, 1H) 10.27 (s, 1H).

3-Methyl-thiophene-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H64)

H64 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-methylthiophene-2-carbonyl chloride. LCMS (m/z): 274 (M+H); ¹H NMR(400 MHz, DMSO-d6) δ ppm 2.46 (s, 3H) 4.96 (s, 2H) 7.03 (d, J=4.9 Hz,1H) 7.37 (d, J=8.2 Hz, 1H) 7.66 (d, J=4.9 Hz, 1H) 7.69 (dd, J=8.2, 2.1Hz, 1H) 8.08 (d, J=2.0 Hz, 1H) 9.21 (s, 1H) 9.99 (s, 1H).

4-Methyl-thiophene-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H65)

H65 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-methylthiophene-2-carbonyl chloride. LCMS (m/z): 274 (M+H); ¹H NMR(400 MHz, DMSO-d6) δ ppm 2.2121 (d, J=1.0 Hz, 3H) 4.96 (s, 2H) 7.38 (d,J=8.6 Hz, 1H) 7.44 (t, J=1.2 Hz, 1H) 7.72 (dd, J=8.2, 2.1 Hz, 1H) 7.85(d, J=1.4 Hz, 1H) 8.10 (d, J=1.8 Hz, 1H) 9.22 (s, 1H) 10.19 (s, 1H).

Benzo[b]thiophene-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H66)

H66 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withbenzo[b]thiophene-2-carbonyl chloride. LCMS (m/z): 310 (M+H); ¹H NMR(400 MHz, DMSO-d6) δ ppm 4.98 (s, 2H) 7.42 (d, J=8.2 Hz, 1H) 7.44-7.54(m, 2H) 7.78 (dd, J=8.2, 2.0 Hz, 1H) 7.99-8.04 (m, 1H) 8.04-8.09 (m, 1H)8.16 (d, J=2.0 Hz, 1H) 8.38 (s, 1H) 9.25 (s, 1H) 10.57 (s, 1H).

3-Chloro-benzo[b]thiophene-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H67)

H67 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-chlorobenzo[b]thiophene-2-carbonyl chloride. LCMS (m/z): 344 (M+H); ¹HNMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 2H) 7.43 (d, J=8.2 Hz, 1H)7.59-7.66 (m, 2H) 7.76 (dd, J=8.3, 2.0 Hz, 1H) 7.92-7.98 (m, 1H)8.11-8.20 (m, 2H) 9.27 (br. s., 1H) 10.58 (s, 1H).

3-Chloro-6-fluoro-benzo[b]thiophene-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H68)

H68 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with3-chloro-6-fluorobenzo[b]thiophene-2-carbonyl chloride. LCMS (m/z): 362(M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 2H) 7.43 (d, J=8.6 Hz,1H) 7.52 (td, J=9.0, 2.4 Hz, 1H) 7.75 (dd, J=8.2, 2.0 Hz, 1H) 7.98 (dd,J=9.0, 5.1 Hz, 1H) 8.07-8.19 (m, 2H) 9.27 (br. s., 1H) 10.57 (s, 1H).

1-Methyl-1H-pyrrole-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H69)

H69 was produced by a similar method as H75 by substitutingpyrazine-2-carboxylic acid with 1-methyl-1H-pyrrole-2-carboxylic acid.

Isoxazole-5-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H70)

H70 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withisoxazole-5-carbonyl chloride. LCMS (m/z): 245 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 4.98 (s, 2H) 7.28 (d, J=2.0 Hz, 1H) 7.42 (d, J=8.2 Hz,1H) 7.76 (dd, J=8.2, 2.0 Hz, 1H) 8.15 (d, J=1.8 Hz, 1H) 8.82 (d, J=1.8Hz, 1H) 10.78 (s, 1H).

4-Methyl-oxazole-5-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H71)

H71 was produced by a similar method as H63 by substitutingthiophene-2-carbonyl chloride with 4-methyloxazole-5-carbonyl chloride.

3-Methyl-thiazolyl-phene-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H72)

This compound was produced by a similar method as H75 by substitutingpyrazine-2-carboxylic acid with 4-methylthiazole-5-carboxylic acid.

1-Methyl-1H-pyrazole-3-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H73)

H73 was produced by a similar method as H75 by substitutingpyrazine-2-carboxylic acid with 1-methyl-1H-pyrazole-3-carboxylic acid.

5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H74)

This compound was produced by a similar method as H75 by substitutingpyrazine-2-carboxylic acid with5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid.

Pyrazine-2-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H75)

To a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (52.1 mg, 0.35mmol), pyrazine-2-carboxylic acid (47.8 mg, 0.385 mmol) and HATU (199.5mg, 0.525 mmol) in DMF (5 mL) was added DIEA (67.85 mg, 0.525 mmol) oneportion, then the mixture was stirred at room temperature overnight. Thesolvent was removed under vacuum and the resulting yellow oil waspurified by prep-HPLC to afford H75.

3,6-Dichloro-pyridazine-4-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H76)

H76 was obtained by a similar procedure to H75 by substitutingpyrazine-2-carboxylic acid with 3,6-dichloropyridazine-4-carboxylicacid.

4-Hydroxy-2-mercapto-pyrimidine-5-carboxylic acid(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (H77)

H77 was obtained by a similar procedure to H75 by substitutingpyrazine-2-carboxylic acid with4-hydroxy-2-mercaptopyrimidine-5-carboxylic acid.

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-acetamide (H78)

H78 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with acetylchloride. LCMS (m/z): 192 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.05(s, 3H) 4.92 (s, 2H) 7.31 (d, J=8.4 Hz, 1H) 7.59 (dd, J=8.2, 2.0 Hz, 1H)7.98 (d, J=1.8 Hz, 1H) 9.18 (s, 1H) 9.93 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,2-dimethyl-propionamide(H79)

H79 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withtrimethylacetyl chloride. LCMS (m/z): 234 (M+H); ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.23 (s, 9H) 7.31 (d, J=8.2 Hz, 1H) 7.61 (dd, J=8.2, 2.0Hz, 1H) 8.00 (d, J=1.8 Hz, 1H) 9.23 (s, 1H).

2-Ethoxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H80)

H80 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-ethoxybenzoyl chloride. LCMS (m/z): 298 (M+H); ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.43 (t, J=6.9 Hz, 3H) 4.20 (q, J=6.9 Hz, 2H) 4.96 (s,2H) 7.01-7.12 (m, 1H) 7.18 (d, J=8.2 Hz, 1H) 7.38 (d, J=8.4 Hz, 1H)7.45-7.55 (m, 1H) 7.74 (dt, J=8.0, 1.9 Hz, 2H) 8.15 (d, J=1.8 Hz, 1H)9.24 (s, 1H) 10.17 (s, 1H).

2-Iodo-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H81)

H81 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-iodobenzoyl chloride. LCMS (m/z): 380 (M+H); ¹H NMR (400 MHz, DMSO-d₆)δ ppm 4.96 (s, 2H) 7.23 (ddd, J=7.9, 6.2, 2.8 Hz, 1H) 7.38 (d, J=8.4 Hz,1H) 7.44-7.58 (m, 2H) 7.70 (dd, J=8.2, 2.0 Hz, 1H) 7.94 (d, J=7.8 Hz,1H) 8.17 (d, J=1.8 Hz, 1H) 9.25 (s, 1H) 10.44 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-nitro-benzamide(H82)

H82 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-nitrobenzoyl chloride. LCMS (m/z): 299 (M+H); ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.98 (s, 2H) 7.30-7.51 (m, 1H) 7.70-7.86 (m, 1H) 8.20 (d,J=8.93 Hz, 3H) 8.38 (d, J=8.79 Hz, 2H) 9.25 (s, 1H) 10.61 (s, 1H).

4-Amino-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide(H83)

In a 50 mL round bottom flask, 5% palladium on carbon was suspended in 3mL of clean, dry THF under nitrogen. H82 (63 mg) was taken up in 2 mL ofdry THF and added slowly to the stirred suspension of catalyst. Glacialacetic acid was added to the reaction mixture, and the system wasdegassed for 1 minute. Hydrogen gas was introduced to the reactionvessel, and the reaction stirred at room temperature for 18 h. Thehydrogen gas was then removed and the system was flushed with N₂. Thiswas repeated three times. The suspension was then diluted with 40 mL ofacetone and the reaction mixture was filtered through Celite. Anadditional 50 mL of acetone was used to wash the Celite. The collectedmixture was then concentrated under reduced pressure, and the resultantyellow oil was then purified using silica gel column chromatography(eluting 100% DCM to 3.5% MeOH in DCM). H83 was isolated as a paleyellow solid. LCMS (m/z)=269 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.95(s, 2H) 5.73 (s, 2H) 6.60 (d, J=8.6 Hz, 2H) 7.34 (d, J=8.2 Hz, 1H) 7.72(d, J=8.5 Hz, 3H) 8.13 (s, 1H) 9.17 (s, 1H) 9.79 (s, 1H).

4-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-N-methyl-benzamide(H84)

To a solution of benzylmethylamine (3.8 mL, 30.0 mmol, 1.0 eq.) and2-bromo-4-fluoro-benzaldehyde (6.1 g, 30.0 mmol, 1.0 eq.) in DMF (100.0mL) was added K₂CO₃ (8.3 g, 60.0 mmol, 2.0 eq.) under nitrogenatmosphere. The mixture was heated at 100° C. overnight. After coolingto room temperature, the mixture was filtered through a short pack ofCelite to remove the solid residue. The filtrate was concentrated underreduced pressure and the residue was purified by silica gelchromatography eluting with EtOAc/heptanes (0:100 to 100:0) to give4-(benzyl-methyl-amino)-2-bromo-benzaldehyde as a fine yellow powder. ¹HNMR (400 MHz, CHLOROFORM-d) δ 10.06 (d, J=0.7 Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.30-7.35 (m, 2H), 7.27 (d, J=7.2 Hz, 1H), 7.14 (d, J=7.3 Hz,2H), 6.85 (d, J=2.5 Hz, 1H), 6.67 (dd, J=8.9, 2.5 Hz, 1H), 4.61 (s, 2H),3.11 (s, 3H). Amount obtained, 7.2 g, 79.0% yield.

To a solution of 4-(benzyl-methyl-amino)-2-bromo-benzaldehyde (7.2 g,23.7 mmol, 1.0 eq.) in 1,4-dioxane (125 mL) was addedbis-pinacol-diboron (6.61 g, 26.0 mmol, 1.1 eq.), KOAc (6.98 g, 71.1mmol, 3.0 eq.) and PdCl₂(dppf)₂ (520 mg, 0.7 mmol, 0.03 eq.). Themixture was degassed with N₂ and heated at 95° C. overnight. Aftercooling to room temperature, the mixture was filtered though a shortpack of Celite and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel chromatography eluting withEtOAc/Heptanes (0:100 to 100:0) to give4-(benzyl-ethyl-amino)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehydeas a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 10.16 (s, 1H), 7.78(d, J=8.8 Hz, 1H), 7.27-7.32 (m, 2H), 7.25 (s, 1H), 7.15 (d, J=7.1 Hz,2H), 7.06 (d, J=2.7 Hz, 1H), 6.74 (dd, J=8.8, 2.6 Hz, 1H), 4.64 (s, 2H),3.12 (s, 3H), 1.36 (s, 12H).

To a suspension of4-(benzyl-ethyl-amino)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde(3.5 g, 10.0 mmol, 1.0 eq.) in EtOH (60 mL) at 0° C. was added NaBH₄(378.3 mg, 10.0 mmol, 1.0 eq.) in small portions. The mixture wasstirred at this temperature for 20 minutes, and then allowed to warm toroom temperature over 1 h. After cooling to 0° C., the clear solutionwas carefully treated with H₂O (1 mL), followed by slow addition of HCl(30 mL, 3N). The resulting yellow suspension was allowed to warm to roomtemperature gradually and stirred for 2 h. The mixture was then treatedwith sat. NaHCO₃ dropwise until the solution reached a final pH of 7.The resultant precipitate was collected by filtration and washed withH₂O to give 6-(benzyl-methyl-amino)-3H-benzo[c][1,2]oxaborol-1-ol as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (s, 1H), 7.28-7.34 (m,2H), 7.20 (q, J=8.9 Hz, 4H), 7.07 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.4,2.5 Hz, 1H), 4.86 (s, 2H), 4.58 (s, 2H), 3.01 (s, 3H).

To a solution of 6-(benzyl-methyl-amino)-3H-benzo[c][1,2]oxaborol-1-ol(506.2 mg, 2.0 mmol, 1.0 eq.) in EtOH (30 mL) was added HCO₂NH₄ (1.2 g,20.0 mmol, 10.0 eq.) and Pd/C (80 mg, 5 mol %). The mixture was heatedto 65° C. in a preheated oil bath under N₂. Upon complete consumption ofthe starting material by TLC, the mixture was cooled to room temperatureand filtered. The filtrate was concentrated under reduced pressure togive 6-methylamino-3H-benzo[c][1,2]oxaborol-1-ol a light yellow solid.The yellow solid was carried forward to the next step without furtherpurification. ¹H NMR (400 MHz, acetone) δ 7.80 (s, 1H), 7.09-7.14 (m,1H), 6.90 (d, J=2.2 Hz, 1H), 6.73-6.78 (m, 1H), 4.87 (s, 2H), 3.79 (s,1H), 2.77 (s, 3H).

To a 20 mL scintillation vial containing6-methylamino-3H-benzo[c][1,2]oxaborol-1-ol (80.9 mg, 0.5 mmol, 1.0 eq.)in DCM (8.0 mL) was added Et₃N (140 μL, 1.0 mmol, 2.0 eq.), followed by4-fluoro-benzoyl chloride (66.9 μL, 0.55 mmol, 1.1 eq.). The resultingwhite suspension was stirred at room temperature over 8 hours beforebeing concentrated under reduced pressure. The residue was purified bysilica gel chromatography, eluting with MeOH/DCM (0:100 to 10:90) togive4-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-N-methyl-benzamideH84 as a white solid. LCMS (m/z) 286 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ9.19 (s, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.30-7.35 (m, 3H), 7.29 (d, J=2.0Hz, 1H), 7.06 (t, J=8.9 Hz, 2H), 4.93 (s, 2H), 3.37 (s, 3H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-N-methyl-benzamide(H85)

H85 was prepared using a procedure similar to that of H84 bysubstituting 4-fluorobenzoyl chloride with 4-methoxybenzoyl chloride.LCMS (m/z): 298 (M+H); ¹H NMR (400 MHz, acetone) δ 8.09 (br. s., 1H),7.46 (d, J=1.9 Hz, 1H), 7.29-7.34 (m, 1H), 7.21-7.27 (m, 3H), 6.67-6.72(m, 2H), 4.96 (s, 2H), 3.71 (s, 3H), 3.39 (s, 3H).

4-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-N-methyl-benzamide(H86)

H86 was prepared using a procedure similar to that of H84 bysubstituting 4-fluorobenzoyl chloride with 4-chlorobenzoyl chloride.LCMS (m/z): 302 (M+H); ¹H NMR (400 MHz, acetone) δ 8.02 (d, J=8.6 Hz,1H), 7.53 (d, J=8.5 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.27-7.33 (m, 3H),7.18-7.24 (m, 2H), 4.95 (s, 2H), 3.42 (s, 3H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4,N-dimethyl-benzamide(H87)

H87 was prepared using a procedure similar to that of H84 bysubstituting 4-fluorobenzoyl chloride with 4-methylbenzoyl chloride.LCMS (m/z): 282 (M+H); ¹H NMR (400 MHz, acetone) δ 7.91 (d, J=8.2 Hz,1H), 7.46 (d, J=1.8 Hz, 1H), 7.28-7.33 (m, 1H), 7.22-7.27 (m, 1H), 7.18(d, J=8.2 Hz, 2H), 6.97 (d, J=7.9 Hz, 2H), 4.95 (s, 2H), 3.40 (s, 3H),2.20 (s, 3H).

2,4-Difluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-N-methyl-benzamide(H88)

H88 was prepared using a procedure similar to that of H84 bysubstituting 4-fluorobenzoyl chloride with 2,4-difluorobenzoyl chloride.LCMS (m/z): 304 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ 9.17 (s, 1H),7.42-7.49 (m, 2H), 7.18-7.30 (m, 2H), 6.89-7.10 (m, 2H), 4.87 (s, 2H),3.33 (s, 3H).

2-(4-Chlorophenyl)-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-acetamide(H89)

H89 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-chlorophenylacetyl chloride. LCMS (m/z) 302 [M+H]; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.66 (s, 2H) 4.93 (s, 2H) 7.20-7.48 (m, 5H) 7.61 (dd,J=8.3, 2.0 Hz, 1H) 7.98 (d, J=1.8 Hz, 1H) 9.18 (s, 1H) 10.20 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-(4-methoxy-phenyl)-acetamide(H90)

H90 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-methoxyphenylacetyl chloride. LCMS (m/z) 298 [M+H]; ¹H NMR (400 MHz,acetone) δ ppm 3.30 (s, 1H) 3.61 (s, 2H) 3.77 (s, 3H) 4.96 (s, 2H) 6.88(d, J=8.8 Hz, 2H) 7.18-7.39 (m, 3H) 7.63 (d, J=2.0 Hz, 1H) 8.03 (d,J=0.6 Hz, 1H) 9.22 (br. s., 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-phenyl-butyramide(H91)

H91 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with2-phenylbutyroyl chloride. LCMS (m/z) 296 [M+H]; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.87 (t, J=7.3 Hz, 3H) 1.46-1.87 (m, 1H) 1.94-2.20 (m,1H) 3.58 (dd, J=8.6, 6.4 Hz, 1H) 4.91 (s, 2H) 7.17-7.28 (m, 1H)7.27-7.36 (m, 3H) 7.40 (d, J=7.2 Hz, 2H) 7.57 (dd, J=8.2, 2.0 Hz, 1H)8.00 (dd, J=1.7, 0.5 Hz, 1H) 9.16 (s, 1H) 10.09 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-phenyl-acetamide(H92)

H92 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withphenylacetyl chloride. LCMS (m/z) 268 [M+H]; ¹H NMR (400 MHz, DMSO-d₆) dppm 3.64 (s, 2H) 4.93 (s, 2H) 7.17-7.29 (m, 1H) 7.27-7.44 (m, 5H) 7.61(dd, J=8.2, 2.0 Hz, 1H) 7.98 (d, J=1.8 Hz, 1H) 9.17 (s, 1H) 10.17 (s,1H).

2-(4-Fluoro-phenyl)-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-acetamide(H93)

H93 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride with4-fluorophenylacetyl chloride. LCMS (m/z) 286 [M+H]; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.64 (s, 2H) 4.93 (s, 2H) 7.15 (t, J=8.9 Hz, 2H)7.24-7.45 (m, 3H) 7.61 (dd, J=8.2, 2.1 Hz, 1H) 7.98 (d, J=1.8 Hz, 1H)9.17 (s, 1H) 10.17 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-phenyl-propionamide(H94)

H94 was prepared using a procedure similar to that of H17 bysubstituting 5-fluoro-2-(trifluoromethyl)benzoyl chloride withhydrocinnamoyl chloride. LCMS (m/z) 282 [M+H]; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.63 (t, J=7.7 Hz, 2H) 2.92 (t, J=7.6 Hz, 2H) 4.92 (s, 2H)7.14-7.22 (m, 1H) 7.23-7.35 (m, 5H) 7.59 (dd, J=8.3, 2.1 Hz, 1H) 7.99(d, 1H) 9.18 (s, 1H) 9.91 (s, 1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-p-tolyl-acetamide(H95)

H95 was prepared using a procedure similar to that of H6 by substituting4-fluorobenzoic acid with 4-methylphenylacetic acid. LCMS (m/z) 282[M+H]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H) 3.57 (s, 2H) 4.90(s, 2H) 7.11 (d, J=7.8 Hz, 2H) 7.21 (d, 2H) 7.30 (d, J=8.4 Hz, 1H) 7.59(dd, J=8.2, 2.0 Hz, 1H) 7.96 (d, J=1.6 Hz, 1H) 9.15 (s, 1H) 10.11 (s,1H).

N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-(7-methoxy-2-oxo-2H-chromen-4-yl)-acetamide(H96)

H96 was prepared using a procedure similar to that of H6 by substituting4-fluorobenzoic acid with 7-methoxycoumarin-4-acetic acid. LCMS (m/z):366 (M+H); ¹H NMR (400 MHz, Acetone-d6) δ ppm 3.92 (s, 3H) 3.99 (s, 2H)4.97 (s, 2H) 6.32 (s, 1H) 6.90 (d, J=2.3 Hz, 1H) 6.94 (dd, J=8.8, 2.5Hz, 1H) 7.34 (d, J=8.2 Hz, 1H) 7.64 (dt, J=8.3, 1.6 Hz, 1H) 7.82 (d,J=9.0 Hz, 2H) 8.01-8.05 (m, 1H) 9.53 (br. s., 1H).

4-Benzyloxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-butyramide(H97)

To a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (74.5 mg, 0.5mmol), 4-(benzyloxy)butanoic acid (128.2 mg, 0.55 mmol) and HATU (285mg, 0.75 mmol) in DMF (8 mL) was added DIEA (96.93 mg, 0.75 mmol) oneportion, then the mixture was stirred at room temperature overnight. Thesolvent was removed under vacuum and the resulting yellow oil waspurified by prep-HPLC to afford H97 as a yellow powder (103.7 mg, yield63.8%).

4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-butyramide(H98)

A suspension of H97 (60 mg, 0.185 mmol) and 10% Pd—C (12 mg) in EtOH (8mL) was stirred under an atmosphere of hydrogen at room temperatureovernight. Then the catalyst was filtered off and the filtrate was thenconcentrated in vacuum to afford the title compound.

6-N-phenylformamide-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (H99)

To a solution of NaOH (2.32 g, 58.0 mmol) in water (10 mL) was addedsilver nitrate (416 mg, 2.46 mmol) in water (3 mL). The mixture wasstirred for 5 minutes at room temperature and cooled to 0° C. To themixture under stirring was added compound 123 (200 mg, 1.33 mmol) inportions. The reaction was conducted at 0° C. for 2 hours beforefiltration. The filtrate was acidified with 1 M HCl to pH 3 andextracted with ethyl acetate. The extracts were dried over Na₂SO₄ andevaporated to give the carboxylic acid intermediate (175 mg, 0.98 mmol,79.6% yield).

To a mixture of the carboxylic acid intermediate (175 mg, 0.98 mmol) andaniline (1084, 1.18 mmol, 1.2 eq) in DCM (8 mL) were added EDCI (377 mg,1.97 mmol, 2.0 eq) and DMAP (5 mg, 0.04 mmol, 0.04 eq). The mixture wasstirred at room temperature for 60 hours before evaporation. The residuewas dissolved in ethyl acetate, and washed with 1 M HCl and brine. Theresidue after evaporation was purified by column chromatography oversilica gel to give the title compound (128 mg, 51.6% yield). ¹H NMR (400MHz, DMSO-d₆): δ 10.29 (s, 1H), 9.34 (s, 1H), 8.30 (d, J=0.8 Hz, 1H),8.03 (dd, J=8 & 1.6 Hz, 1H), 7.77 (dd, J=8 & 0.8 Hz, 2H), 7.54 (d, J=8Hz, 1H), 7.34 (t, J=8 Hz, 1H), 7.08 (t, J=8 Hz, 1H) and 5.06 (s, 2H)ppm.

Alternate synthesis of1-hydroxy-N-phenyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide

Synthesis of 3-bromo-4-(hydroxymethyl)benzonitrile (B)

A solution of 3-bromo-4-formylbenzonitrile A (1.0 g, 4.8 mmol) in CH₃OH(30 mL) was cooled to 0° C. NaBH₄ (180 mg, 4.8 mmol) was addedportionwise. The mixture was allowed to warm to room temperature andstir at room temperature for 1 h. The mixture was quenched with 1N HCland concentrated under vacuum. The residue was extracted with ethylacetate (25 mL*3). The combined organic layers were washed with brine(20 mL), dried (Na₂SO₄) and concentrated under vacuum to give a whitesolid of the desired compound B (1.0 g, 99%). ¹H NMR (300 MHz, CDCl₃): δ7.82 (s, 1H), 7.49-7.71 (m, 2H), 4.75 (s, 2H). LC-MS: 212 (M+1)⁺.

Synthesis of 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonitrile(C)

A solution of compound B (211 mg, 1.0 mmol) and triisopropyl borate (282mg, 1.5 mmol) in anhydrous THF (10 mL) at N₂ atmosphere was cooled to−78° C. n-BuLi (0.9 mL, 2.25 mmol) was added dropwise at −78° C. Thenthe mixture was allowed to warm to room temperature and stir at roomtemperature for 1 h. The mixture was quenched with 1N HCl and extractedwith ethyl acetate (25 mL*3). The combined organic layers were washedwith brine (20 mL), dried (Na₂SO₄) and concentrated under vacuum. Theresidue was purified by column chromatography (eluting with CH₃OH andEtOAc=1:1) on silica gel to give the desired compound C as a yellowsolid (80 mg, 50%). ¹H NMR (300 MHz, CDCl₃): δ 9.50 (s, 1H), 8.08 (s,1H), 7.83-7.92 (m, 1H), 7.61-7.66 (m, 1H), 5.06 (s, 2H). LC-MS: 160(M+1)⁺.

Synthesis of 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylicacid (D)

A solution of compound C (100 mg, 0.63 mmol) in conc. HCl (10 mL) wasrefluxed for 3 h and cooled to RT. The mixture was filtrated. The solidwas washed with water, dried to give the product D as a white solid (95mg, 85%). ¹H NMR (300 MHz, DMSO-d₆): δ 12.92 (s, 1H), 9.36 (s, 1H), 8.10(s, 1H), 8.05 (d, 1H), 7.54 (d, 1H), 5.08 (s, 2H). LC-MS: 177 (M−1)⁺.Purity on HPLC: 50.5% (214 nm).

Synthesis of1-hydroxy-N-phenyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide

A solution of compound C (20 mg, 0.11 mmol), HATU (46.5 mg, 0.12 mmol)and DIEA (52.4 mg, 0.40 mmol) in dry DMF (2 mL) is stirred for 1 hbefore the addition of a solution of aniline (0.10 mmol), DMAP (50 mg,0.40 mmol) and DBU (62 mg, 0.40 mmol) in dry DMF (1 mL). The reactionmixture is stirred at room temperature overnight and diluted with EtOAc(100 mL) and is washed with aqueous NaOAc buffer (30 mL*2), 5% NaHCO₃(30 mL) and brine (50 mL). The organic layer is dried over Na₂SO₄ and isconcentrated. The residue is purified by prep-HPLC to give the titlecompound.

6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol (H100)

The title compound was synthesized as shown in the scheme.

Synthesis of 2-bromo-4-(4-chlorophenylthio)benzaldehyde (B)

A mixture of 4-chlorophenylthiol (10 g, 69.15 mmol),2-bromo-4-fluorobenzaldehyde (14.04 g, 69.15 mmol) and K₂CO₃ (19 g) indry DMF (150 mL) was heated to 100° C. and stirred for 4 h. The mixturewas filtered and the filtrate was evaporated to remove the solvent. Theresidue was dissolved in Et₂O and filtered to remove insoluble solid.Again, the filtrate was evaporated to give a brown liquid that becamesolid after being pumped on vacuum (22.17 g, yield 97.9%). ¹H NMR (300Hz, DMSO-d₆): δ 10.08 (s, 1H), 7.72 (d, 1H), 7.57 (s, 4H), 7.43 (s, 1H)and 7.21 (d, 1H) ppm.

Synthesis of (2-bromo-4-(4-chlorophenylthio)phenyl)methanol (C)

2-Bromo-4-(4-chlorophenylthio)benzaldehyde (22.1 g, 67.45 mmol) inmethanol (300 mL) was reduced with NaBH₄ (3.1 g) at 0° C. for 20 minafter the completion of NaBH₄ addition. A normal work-up andpurification by silica gel column chromatography (hexane:EtOAc=5; 1,v/v) provided the desired alcohol (19.8 g, yield 89%) as a white solid.¹H NMR (300 Hz, DMSO-d₆): δ 7.54-7.50 (m, 2H), 7.43 (d, 2H), 7.37 (dd,1H), 7.32 (d, 2H), 5.49 (t, 1H) and 4.48 (d, 2H) ppm.

Synthesis of(3-bromo-4-((methoxymethoxy)methyl)phenyl)(4-chlorophenyl)sulfane (D)

To a solution of (2-bromo-4-(4-chlorophenylthio)phenyl)methanol (20 g,61.3 mmol) and N,N-diisopropyl-N-ethyl amine (184 mmol) in DCM (200 mL)was added dropwise methoxymethyl chloride (MOM-Cl, 14.7 g, 184 mmol) at0° C. under N₂. The mixture was stirred at r.t. for 2 days. The mixturewas washed with water and concentrated under vacuum to give a cruderesidue, which was purified by column to afford the desired product as awhite solid (16 g, yield 70%).

Synthesis of2-bromo-4-(4-chlorophenylsulfinyl)-1-((methoxymethoxy)methyl)benzene (E)

To a solution of(3-bromo-4-((methoxymethoxy)methyl)phenyl)(4-chlorophenyl)sulfane (16 g,43 mmol) in DCM (100 mL) was added NaIO₄ (10.1 g, 47.3 mmol) at 0° C.under N₂. The mixture was stirred at r.t. for 1 hour. The mixture waswashed with water and the organic layer was concentrated under vacuum togive the crude residue that was purified by column chromatography toafford the desired product as a white solid (10 g, yield 64%). ¹H NMR(300 MHz, CDCl₃) δ 7.81 (d, J=1.5 Hz, 1H), 7.60-7.55 (m, 4H), 7.44 (d,J=8.7 Hz, 2H), 4.75 (s, 2H), 4.63 (s, 2H), 4.00 (s, 3H) ppm.

Synthesis of 6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol(F) from compound E

To a solution of2-bromo-4-(4-chlorophenylsulfinyl)-1-((methoxymethoxy)methyl)-benzene(10 g, 37.5 mmol) in dioxane (100 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (11.4 g, 45mmol), Pd(dppf)₂Cl₂ (765 mg, 2.5 mol %), and KOAc (11 g, 112.5 mmol) atr.t. under N₂. The mixture was stirred at 70° C. for 10 hours. Themixture was filtered and the filtrate was extracted with EtOAc. Thecombined organic layers were concentrated in vacuo to give the cruderesidue, which was purified by column chromatography to provide2-(5-(4-chlorophenylsulfinyl)-2-((methoxymethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a white solid (10 g, yield 70%). ¹H NMR (300 MHz, CDCl₃) δ 8.05 (d,J=1.8 Hz, 1H), 7.70-7.56 (m, 4H), 7.31 (d, J=8.4 Hz, 2H), 4.84 (s, 2H),4.72 (s, 2H), 3.38 (s, 3H), 1.33 (s, 12H) ppm.

This pinacol-boron intermediate (10 g, 22.3 mmol) and 6N HCl (200 mL)were stirred at rt overnight. The precipitate was filtered and the solidwas dried to give the desired title compound as a white power (6 g,89.5%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.08 (s, 1H), 7.80(dd, J=7.8, 1.2 Hz, 1H), 7.72 (d, 2H), 7.61 (d, 2H), 7.56 (d, 1H) and5.01 (s, 2H) ppm. The data are consistent with the NMR of the compoundgenerated with another method described above.

6-(3-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol (H101)

Compound 28 (1.45 mmol) was dissolved in 10% (v/v) H₂O in MeOH (30 mL).To this solution was added sodium periodate (3.2 g, 14.5 mmol, 10.0 eq).The reaction mixture was stirred for 12 hours then treated with 1 M HCl(10 ml). After extraction with ethyl acetate, the organic layer waswashed with water and brine, and dried over anhydrous Na₂SO₄. Afterrotary evaporation the residue was purified by crystallization to givethe title compound (275 mg, 65% yield). ¹H NMR (300 MHz, DMSO-d₆): δ9.39 (s, 1H), 8.11 (s, 1H), 7.85 (dd, J=8.1 & 1.8 Hz, 1H), 7.78 (s, 1H),7.69-7.63 (m, 1H), 7.59-7.56 (m, 3H) and 5.01 (s, 2H) ppm. Mp 152-153°C.

6-(2-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol (H102)

This compound was produced by the same method as H101 by substituting4-chlorophenylthiol with 2-chlorophenylthiol. ¹H NMR (300 MHz, DMSO-d₆):δ 9.41 (s, 1H), 8.09 (d, J=1.2 Hz, 1H), 8.01-7.97 (m, 1H), 7.83 (dd,J=8.1 & 1.8 Hz, 1H), 7.71-7.65 (m, 1H), 7.61-7.51 (m, 3H) and 5.02 (s,2H) ppm. MS: found: 315 (M+Na)⁺, 347 (M+Na+MeOH)⁺. Mp 174-175° C.

6-(4′-chlorophenylsulfanyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H103)

The synthesis of the title compound has been described previously inU.S. patent application Ser. Nos. 11/357,687; 11/505,591 and 11/676,120.

6-(3′-chlorophenylsulfanyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H104)

2-bromo-4-(3-chlorophenylsulfanyl)benzaldehyde (25)

Compound 24 (7.39 mmol) was dissolved in DMF (25 mL) and cooled to 0° C.with ice bath. To this solution under nitrogen were added in sequencepotassium carbonate (2.04 g, 14.78 mmol, 2.0 eq) and3-chlorobenzenethiol (0.835 ml, 7.39 mmol, 1.0 eq). The reaction mixturewas stirred for 0.5 hour then treated with cooled water (50 ml). Afterextraction with ethyl acetate, the organic layer was washed with waterand brine, and dried over anhydrous Na₂SO₄. The residue after rotaryevaporation was purified by column chromatography over silica gel togive compound 25 (1.92 g, 80% yield). ¹H NMR (400 MHz, CDCl₃): δ 10.25(s, 1H), 7.78 (d, J=8 Hz, 1H) and 7.52-7.12 (m, 6H) ppm.

2-bromo-4-(3′-chlorophenylthio)benzyl alcohol (26)

Compound 25 (6.08 mmol) was dissolved in MeOH (25 mL) and cooled to 0°C. with ice bath. To this solution was added NaBH₄ (459.6 mg, 12.16mmol, 2.0 eq). The reaction mixture was stirred for 0.5 hour thentreated with saturated NaHCO₃. After evaporation, the residue wasextracted with ethyl acetate, washed with water and brine, and driedover anhydrous Na₂SO₄. The residue after rotary evaporation was purifiedby column chromatography over silica gel to give compound 26 (1.8 g, 90%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.60-7.23 (m, 7H), 5.53 (t, J=5.2Hz, 1H) and 4.51 (d, J=5.2 Hz, 2H) ppm.

(3-bromo-4-((methoxymethoxy)methyl)phenyl)(3-chlorophenyl)sulfane (27)

Compound 26 (5.94 mmol) was dissolved in anhydrous CH₂Cl₂ (25 mL). Tothis solution under nitrogen were added in sequenceN,N-diisopropylethylamine (3.67 ml, 20.79 mmol, 3.5 eq) and chloromethylmethyl ether (0.96 mL, 13.07 mmol, 2.2 eq). The reaction mixture wasstirred for 14 hours then treated with water (10 ml). After extractionwith dichloromethane, the organic layer was washed with water and brine,and dried over anhydrous Na₂SO₄. After rotary evaporation, the residuewas purified by column chromatography over silica gel to give compound27 (1.79 g, 80% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, J=1.6 Hz,1H), 7.46 (d, J=8.0 Hz, 1H), 7.32-7.17 (m, 5H), 4.77 (s, 2H), 4.64 (s,2H) and 3.43 (s, 3H) ppm.

6-(3′-chlorophenylsulfanyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

Compound 27 (1.0 g, 2.67 mmol) was dissolved in anhydrous THF (20 mL)and cooled to −80° C. To this solution under nitrogen was added dropwise1.6M n-BuLi (1.84 mL, 2.94 mmol, 1.1 eq) over 20 minutes. After stirringfor another 20 minutes at −80° C., B(iPrO)₃ (0.68 mL, 2.94 mmol, 1.1 eq)was added dropwise over 8 minutes. The reaction mixture was allowed towarm to room temperature gradually and stirred overnight at roomtemperature. After 6M HCl (10 mL) was added and stirred for 2 hours, themixture was evaporated and extracted with ethyl acetate (25 mL×5) anddried over anhydrous Na₂SO₄. The residue after rotary evaporation waspurified by column chromatography over silica gel to give the titlecompound (380 mg, 51.5% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.30 (s,1H), 7.81 (d, J=1.6 Hz, 1H), 7.58 (dd, J=8 & 1.6 Hz, 1H), 7.5 (d, J=8Hz, 1H), 7.45-7.15 (m, 4H) and 5.02 (s, 2H) ppm.

6-(2′-chlorophenylsulfanyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H105)

This compound was produced by the same method as H104 by substituting3-chlorobenzenethiol with 2-chlorobenzenethiol. ¹H NMR (300 MHz,DMSO-d₆): δ 9.30 (s, 1H), 7.80 (d, J=0.9 Hz, 1H), 7.50-7.59 (m, 3H),7.25 (m, 2H), 6.91 (m, 1H) and 5.03 (s, 2H) ppm. MS: found: 275 (M−H)⁻.Mp 116-118° C.

6-(4′-chlorophenylsulfanyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H106)

The synthesis of the title compound has been described previously inU.S. patent application Ser. Nos. 11/357,687; 11/505,591 and 11/676,120.

6-(3′-chloro)phenylsulfonyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H107)

1-(3′-bromo-4′-((methoxymethoxy)methyl)phenylsulfonyl)-3-chlorobenzene(30)

Compound 27 (4.78 mmol) was dissolved in CH₂Cl₂ (45 mL) and cooled to 0°C. with ice bath. To this solution was added meta-chloroperoxybenzoicacid (2.48 g, 14.36 mmol, 3.0 eq). The reaction mixture was stirred for18 hours then treated with 1.25M NaOH (20 ml). After evaporation theresidue was extracted with ethyl acetate, washed with water and brine,and dried over anhydrous Na₂SO₄. The residue after rotary evaporationwas purified by column chromatography over silica gel to give compound30 (1.5 g, 77% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.24 (d, J=1.8 Hz,1H), 8.11-7.97 (m, 6H), 4.72 (s, 2H), 4.60 (s, 2H) and 3.29 (s, 3H) ppm.

6-(3′-chloro)phenylsulfonyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

Compound 30 (1.0 g, 2.46 mmol) was dissolved in anhydrous THF (16 mL)and cooled to −80° C. To this solution under nitrogen was added dropwise1.6M n-BuLi (1.69 mL, 2.71 mmol, 1.1 eq) over 20 minutes. After stirringfor 20 minutes at −80° C., B(iPrO)₃ (0.62 mL, 2.71 mmol, 1.1 eq) wasadded dropwise over 8 minutes. The reaction mixture was allowed to warmto room temperature gradually and stirred overnight at room temperature.After 6M HCl (10 mL) was added and stirred for 2 hours, the mixture wasevaporated, extracted with ethyl acetate (25 mL×5) and dried overanhydrous Na₂SO₄. The residue after rotary evaporation was purified bycrystallization to give the title compound (123 mg, 16.2% yield). ¹H NMR(300 MHz, DMSO-d₆): δ 9.48 (s, 1H), 8.35-7.63 (m, 7H), and 5.06 (s, 2H)ppm.

6-(2′-chlorophenylsulfanyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H108)

This compound was produced by the same method as H104 by substituting3-chlorobenzenethiol with 2-chlorobenzenethiol. ¹H NMR (300 MHz,DMSO-d₆): δ 9.50 (s, 1H), 8.35-8.30 (m, 2H), 8.00 (dd, J=8.1 & 1.8 Hz,1H), 7.78-7.62 (m, 4H) and 5.08 (s, 2H) ppm. MS: found: 331 (M+Na)⁺, 363(M+Na+MeOH)⁺. Mp 130-132° C.

6-(3′,4′-dichlorophenyl)sulfenyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H109)

2-bromo-4-(3′,4′-dichlorophenylsulfanyl)benzaldehyde (32)

Compound 24 (14.78 mmol) was dissolved in DMF (70 mL) and cooled to 0°C. with ice bath. To this solution under nitrogen were added in sequencepotassium carbonate (4.08 g, 29.55 mmol, 2.0 eq) and3,4-dichlorobenzenethiol (1.88 ml, 14.78 mmol, 1.0 eq). The reactionmixture was stirred for 0.5 hour then treated with cooled water (100ml). After extraction with ethyl acetate the organic layer was washedwith water and brine, and dried over anhydrous Na₂SO₄. The residue wasevaporated to give compound 32 (4.49 g, 84% yield).

(2-bromo-4-(3′,4′-dichlorophenylsulfanyl)benzyl alcohol (33)

Compound 32 (12.46 mmol) was dissolved in MeOH (50 mL) and cooled to 0°C. with ice bath. To this solution was added NaBH₄ (942 mg, 24.93 mmol,2.0 eq). The reaction mixture was stirred for 0.5 hour then treated withsaturated NaHCO₃. After evaporation the residue was extracted with ethylacetate, washed with water and brine, and dried over anhydrous Na₂SO₄.The residue was evaporated to give compound 33 (4.3 g, 95% yield).

(3-bromo-4-((methoxymethoxy)methyl)phenyl)(3,4-dichlorophenyl)sulfane(34)

Compound 33 (11.84 mmol) was dissolved in anhydrous CH₂Cl₂ (50 mL). Tothis solution under nitrogen were added in sequenceN,N-Diisopropylethylamine (7.32 ml, 41.45 mmol, 3.5 eq) and chloromethylmethyl ether (1.91 mL, 26.05 mmol, 2.2 eq). The reaction mixture wasstirred for 14 hours then treated with water (15 ml). After extractionwith dichloromethane, the organic layer was washed with water and brine,and dried over anhydrous Na₂SO₄. After rotary evaporation the residuewas purified by column chromatography over silica gel to give compound34 (4.04 g, 83% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.66-7.58 (m, 3H),7.53 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4 & 2 Hz, 1H), 7.28-7.25 (m, 1H),4.71 (s, 2H), 4.55 (s, 2H) and 3.31 (s, 3H) ppm

6-(3′,4′-dichlorophenyl)sulfenyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

Compound 34 (2.39 g, 5.86 mmol) was dissolved in anhydrous THF (25 mL)and cooled to −80° C. To this solution under nitrogen was added dropwise1.6M n-BuLi (4.03 mL, 6.45 mmol, 1.1 eq) over 20 minutes. After stirredfor another 20 minutes at −80° C., B(iPrO)₃ (1.48 mL, 6.45 mmol, 1.1 eq)was added dropwise over 8 minutes. The reaction mixture was allowed towarm to room temperature gradually and stirred overnight at roomtemperature. After 6M HCl (20 mL) was added and stirred overnight, themixture was evaporated and extracted with ethyl acetate (25 mL×5) anddried over anhydrous Na₂SO₄. The residue after rotary evaporation waspurified by column chromatography over silica gel to give the titlecompound (607.5 mg, 33.3% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.28 (s,1H), 7.81 (s, 1H), 7.60-7.45 (m, 4H), 7.15 (dd, J=8.4 & 2 Hz, 1H) and5.03 (s, 2H) ppm.

6-(2′,3′-dichlorophenyl)sulfenyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H110)

This compound can be produced by the same method as H109 by substituting3,4-dichlorobenzenethiol with 2,3-dichlorobenzenethiol.

6-(2′,4′-dichlorophenyl)sulfenyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H111)

This compound was produced by the same method as H109 by substituting3,4-dichlorobenzenethiol with 2,4-dichlorobenzenethiol. ¹H NMR (400 MHz,DMSO-d₆): δ 9.30 (s, 1H), 7.79 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.54 (m,2H), 7.33 (dd, J=8.4 & 2.0 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H) and 5.02 (s,2H) ppm. MS: found: 309 (M+1)⁺. Mp 125-127° C.

6-(2′,5′-dichlorophenyl)sulfenyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H112)

This compound can be produced by the same method as H109 by substituting3,4-dichlorobenzenethiol with 2,5-dichlorobenzenethiol.

6-(2′,6′-dichlorophenyl)sulfenyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H113)

This compound can be produced by the same method as H109 by substituting3,4-dichlorobenzenethiol with 2,6-dichlorobenzenethiol.

6-(3′,4′-dichlorophenyl)sulfinyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H114)

6-(3′,4′-dichlorophenyl)sulfinyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(36)

Compound 35 (0.64 mmol) was dissolved in 10% (v/v) H₂O in MeOH (15 mL).To this solution was added sodium periodate (688 mg, 3.21 mmol, 5.0 eq).The reaction mixture was stirred for 12 hours then evaporated andextracted with ethyl acetate. The organic layer was washed with waterand brine, and dried over anhydrous Na₂SO₄. After rotary evaporation theresidue was purified by crystallization to give the title compound(112.4 mg, 53.5% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.11(s, 1H), 7.99 (d, J=2 Hz, 1H), 7.88-7.81 (m, 2H), 7.69-7.60 (m, 2H) and5.02 (s, 2H) ppm.

6-(2′,3′-dichlorophenyl)sulfinyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H115)

This compound can be produced by the same method as H114 by substituting3,4-dichlorobenzenethiol used in making compound 35 with2,3-dichlorobenzenethiol.

6-(2′,4′-dichlorophenyl)sulfinyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H116)

This compound was produced by the same method as H114 by substituting3,4-dichlorobenzenethiol used in making compound 35 with2,4-dichlorobenzenethiol. ¹H NMR (300 MHz, DMSO-d₆): δ 9.41 (s, 1H),8.07 (d, J=1.5 Hz, 1H), 7.97 (m, 1H), 7.83 (dd, J=8.1 & 1.8 Hz, 1H),7.78 (m, 2H), 7.58 (d, J=8.1 Hz, 1H) and 5.03 (s, 2H) ppm. MS: found:327 (M−1)⁻. Mp 155-157° C.

6-(2′,5′-dichlorophenyl)sulfinyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H117)

This compound can be produced by the same method as H114 by substituting3,4-dichlorobenzenethiol used in making compound 35 with2,5-dichlorobenzenethiol.

6-(2′,6′-dichlorophenyl)sulfinyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H118)

This compound can be produced by the same method as H114 by substituting3,4-dichlorobenzenethiol used in making compound 35 with2,6-dichlorobenzenethiol.

6-(3′,4′-dichlorophenyl)sulfonyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H119)

6-(3′,4′-dichlorophenyl)sulfonyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

Compound 35 (0.83 mmol) was dissolved in 10% (v/v) H₂O in MeOH (20 mL).To this solution was added sodium periodate (894 mg, 4.17 mmol, 6.5 eq).The mixture was stirred for 2 days at 65° C. then evaporated andextracted with ethyl acetate, the organic layer was washed with waterand brine, and dried over anhydrous Na₂SO₄. After rotary evaporation,the residue was purified by crystallization to give the title compound(86 mg, 30% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.49 (s, 1H), 8.35 (s,1H), 8.20 (s, 1H), 8.12 (dd, J=8.4 & 2 Hz, 1H), 7.90 (d, J=1.2 Hz, 2H),7.68 (d, J=8.4 Hz, 1H), and 5.06 (s, 2H) ppm.

6-(2′,3′-dichlorophenyl)sulfonyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H120)

This compound can be produced by the same method as H119 by substituting3,4-dichlorobenzenethiol used in making compound 35 with2,3-dichlorobenzenethiol.

6-(2′,4′-dichlorophenyl)sulfonyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H121)

This compound was produced by the same method as H119 by substituting3,4-dichlorobenzenethiol used in making compound 35 with2,4-dichlorobenzenethiol. ¹H NMR (300 MHz, DMSO-d₆): δ 9.49 (s, 1H),8.31 (d, J=8.7 Hz, 2H), 8.00 (dd, J=8.4 & 2.1 Hz, 1H), 7.87 (d, J=1.8Hz, 1H), 7.80 (dd, J=8.7 & 2.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H) and 5.09(s, 2H) ppm. Mp 169-171° C.

6-(2′,5′-dichlorophenyl)sulfonyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H122)

This compound can be produced by the same method as H119 by substituting3,4-dichlorobenzenethiol used in making compound 35 with2,5-dichlorobenzenethiol.

6-(2′,6′-dichlorophenyl)sulfonyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H123)

This compound can be produced by the same method as H119 by substituting3,4-dichlorobenzenethiol used in making compound 35 with2,6-dichlorobenzenethiol.

6-(phenylthio)benzo[c][1,2]oxaborol-1(3H)-ol (H124)

The synthesis of the title compound has been described previously inU.S. patent application Ser. Nos. 11/357,687; 11/505,591 and 11/676,120.

6-(phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (H125)

The synthesis of the title compound has been described previously inU.S. patent application Ser. Nos. 11/357,687; 11/505,591 and 11/676,120.

N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-benzamide (H126)

The synthesis of the title compound has been described previously inU.S. patent application Ser. Nos. 11/357,687; 11/505,591 and 11/676,120.Alternatively, the title compound can be synthesized according to themethods described above by using benzoyl chloride in place of2-(trifluoromethyl)benzoyl chloride.

N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-benzamine (H127)

The synthesis of the title compound has been described previously inU.S. patent application Ser. Nos. 11/357,687; 11/505,591 and 11/676,120.

6-(phenylsulfonamido)benzo[c][1,2]oxaborol-1(3H)-ol (H128)

The synthesis of the title compound has been described previously inU.S. patent application Ser. Nos. 11/357,687; 11/505,591 and 11/676,120.

6-(phenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol (H129)

The title compound was synthesized according to the methods above byusing phenylthiol in place of 4-chlorophenylthiol.

6-(phenylsulfonyl)benzo[c][1,2]oxaborol-1(3H)-ol (H130)

The title compound was synthesized according to the methods describedabove by using phenylthiol in place of 4-chlorophenylthiol.

[6-(1-phenyl-1-hydroxylmethyl)]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(H131)

(2-bromo-4-benzoyl)toluene (15)

To a mixture of AlCl₃ (1.46 g, 11.0 mmol, 1.1 eq) in benzene (16 mL) wasadded a solution of compound 2 (2.33 g, 10.0 mmol) in benzene (8 mL)dropwise at room temperature. This mixture was stirred for 2 hours at50° C. The mixture was washed with 3M HCl (20 mL) and saturated brine(20 mL), and dried over anhydrous Na₂SO₄. The residue after rotaryevaporation was purified by column chromatography over silica gel togive compound 15 (2.7 g, 98% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.98 (d,J=1.8 Hz, 1H), 7.78 (d, J=6.9 Hz, 2H), 7.65 (dd, J=7.8 & 1.5 Hz, 1H),7.59 (d, J=7.5 Hz, 1H), 7.49 (t, J=7.5 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H)and 2.49 (s, 3H) ppm.

(2-bromomethyl-5-benzoyl)bromobenzene (16)

To a solution of compound 15 (2.7 g, 9.8 mmol) in CCl₄ (50 mL) was addedNBS (1.75 g, 9.8 mmol, 1.0 eq) and Bz₂O₂ (0.12 g, 0.5 mmol, 0.05 eq).This mixture was heated to reflux and stirred overnight. The residueafter rotary evaporation was purified by column chromatography oversilica gel to give compound 16 (1.71 g, 49.3% yield). ¹H NMR (300 MHz,CDCl₃): δ 8.01 (d, J=1.5 Hz, 1H), 7.79 (d, J=7.8 Hz, 2H), 7.71 (dd,J=8.1& 1.5 Hz, 1H) and 4.64 (s, 2H) ppm.

(2-bromo-4-benzoyl)benzyl acetate (17)

To a solution of compound 16 (1.71 g, 4.83 mmol) in DMF (30 mL) wasadded sodium acetate (1.98 g, 24.15 mmol, 5.0 eq). This mixture washeated to 60° C. and stirred overnight. The mixture was poured intoice-water (50 g). The precipitate was filtered, washed with water anddried under vacuum to give compound 17 (1.63 g, 100% yield).

(2-bromo-4-benzoyl)benzyl alcohol (18)

To a solution of compound 17 (1.63 g, 4.9 mmol) in methanol (25 mL) wasadded 15% aq NaOH (5 mL). This mixture was heated to reflux and stirredfor 1 hour. After methanol was evaporated the mixture was extracted withethyl acetate, dried over anhydrous Na₂SO₄. The residue after rotaryevaporation was purified by crystallization to give compound 18 (1.50 g,100% yield).

(2-bromo-4-benzoyl)benzaldehyde (19)

To a solution of compound 18 (1.50 g, 5.15 mmol) in DCM (30 mL) wasadded PCC (2.22 g, 10.3 mmol, 2.0 eq) and celite (2.5 g). This mixturewas stirred overnight at room temperature. Then the mixture was filteredand the residue after rotary evaporation was purified by crystallizationto give compound 19 (1.32 g, 88.7% yield).

[2-(3-bromo-4-(1,3-dioxolan-2-yl)phenyl)-2-phenyl]-1,3-dioxolane (20)

To a solution of compound 19 (1.32 g, 4.57 mmol) in toluene (50 mL) wasadded ethylene glycol (2.83 g, 45.70 mmol, 10.0 eq) andp-toluenesulfonate monohydrate (69 mg, 0.36 mmol, 0.08 eq). This mixturewas heated to reflux and stirred for 96 hours. The mixture was washedwith saturated NaHCO₃, water and brine, dried over anhydrous Na₂SO₄. Thesolvent was evaporated to give compound 20 (1.51 g, 98% yield).

(2-formyl-5-benzoyl)phenylboronic acid (21)

Compound 20 (0.50 g, 1.23 mmol) was dissolved in anhydrous THF (10 mL)and cooled to −80° C. To this solution under nitrogen was added dropwise1.6M n-BuLi (0.88 mL, 1.41 mmol, 1.15 eq) over 15 minutes. After stirredfor another 20 minutes at −80° C., B(iPrO)₃ (0.33 mL, 1.41 mmol, 1.15eq) was added dropwise over 10 minutes. The reaction mixture was allowedto warm to room temperature gradually and stirred overnight at roomtemperature. After 6M HCl (6 mL) was added and stirred for 2 hours, themixture was evaporated and extracted with ethyl acetate (25 mL×5) anddried over anhydrous Na₂SO₄. The residue after rotary evaporation waspurified by column chromatography over silica gel to give compound 21(0.31 g, 88% yield).

[6-(1-phenyl-1-hydroxylmethyl)]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

Compound 21 (0.75 g, 2.95 mmol) was dissolved in THF (8 mL) and water(0.5 mL). To this solution under stirring was added NaBH₄ (217 mg, 5.90mmol, 2.0 eq) at room temperature. After stirred for 3 hours, 3M HCl (10mL) was added to quench the reaction, and the mixture was evaporated andextracted with ethyl acetate (30 mL×3), dried over anhydrous Na₂SO₄. Theresidue after rotary evaporation was purified by crystallization to givethe title compound (0.35 g, 50% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 9.1(s, 1H), 7.71 (s, 1H), 7.46 (dd, J=8.1 & 1.8 Hz, 1H), 7.31 (m, 5H), 7.18(d, J=7.5 Hz, 1H), 5.89 (d, J=3.9 Hz, 1H), 5.72 (d, J=3.6 Hz, 1H) and4.91 (s, 2H) ppm.

6-Benzoyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (H132)

To a solution of compound 22 (0.2 g, 0.83 mmol) in 15 mL DCM was addedPCC (0.45 g, 2.08 mmol, 2.5 eq) and celite (0.45 g). This mixture wasstirred for 3 hours at room temperature before filtration. The residueafter rotary evaporation was purified by crystallization to give thetitle compound (0.15 g, 76% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.35(s, 1H), 8.12 (s, 1H), 7.87 (dd, J=8 & 1.6 Hz, 1H), 7.69 (m, 3H), 7.57(m, 3H) and 5.08 (s, 2H) ppm.

6-Benzyloxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (H133)

2-bromo-4-fluorobenzyl alcohol (38)

Compound 24 (49 mmol) was dissolved in MeOH (100 mL) and cooled to 0° C.with ice bath. To this solution was added NaBH₄ (3.7 g, 98 mmol, 2.0eq). The reaction mixture was stirred for 1 hour then treated withsaturated NaHCO₃. After evaporation, the residue was extracted withethyl acetate and the organic layer was washed with water and brine. Theresidue after rotary evaporation was purified by column chromatographyover silica gel to give compound 38 (9.04 g, 90% yield).

[3-fluoro-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)]bromobenzene (39)

Compound 38 (4.88 mmol) and 3,4-dihydro-2H-pyran (24.4 mmol, 5.0 eq) wasdissolved in DCM (20 mL). To this solution were added in sequencepyridinium p-toluenesulfonate (0.5 mmol, 0.1 eq). The reaction mixturewas stirred overnight at room temperature then treated with saturatedNaHCO₃. After extraction with ethyl acetate, the organic layer waswashed with water and brine. The residue after rotary evaporation waspurified by column chromatography over silica gel to give compound 39(1.2 g, 85.1% yield).

[3-benzyloxy-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)]bromobenzene (40)

Compound 39 (1 mmol) was dissolved in DMF (20 mL) and cooled to 0° C.with ice bath. To this solution under nitrogen were added in sequencesodium hydride (353 mg, 8.8 mmol, 2.5 eq) and benzyl alcohol (0.76 g,7.06 mmol, 2.0 eq). The reaction mixture was stirred for 1 hour at 100°C. then treated with cold water (30 ml). After extraction with ethylacetate, the organic layer was washed with water and brine. The residueafter rotary evaporation was purified by column chromatography oversilica gel to give compound 40 (0.86 g, 64.8% yield). ¹H NMR (300 MHz,CDCl₃): δ 7.39 (m, 6H), 7.20 (dd, J=3.2 Hz, 1H), 6.92 (dd, J=11.2 & 3.2Hz, 1H), 5.04 (s, 2H), 4.79 (s, 0.5H), 4.75 (s, 1.5H), 4.52 (s, 1H),3.93 (m, 1H), 3.55 (m, 1H) and 1.70 (m, 6H) ppm.

Compound 40 (0.86 g, 2.28 mmol) was dissolved in anhydrous THF (200 mL)and cooled to −80° C. To this solution under nitrogen was added dropwise1.6M n-BuLi (1.64 mL, 2.62 mmol, 1.15 eq) over 20 minutes. After themixture was stirred for another 20 minutes at −80° C., B(iPrO)₃ (0.61mL, 2.62 mmol, 1.15 eq) was added dropwise over 8 minutes. The mixturewas allowed to warm to room temperature gradually and stirred overnightat room temperature. After 6M HCl (6 mL) was added and stirred for 2hours, the mixture was evaporated and extracted with ethyl acetate (25mL×5) and dried over anhydrous Na₂SO₄. The residue after rotaryevaporation was purified by crystallization to give the title compound(0.36 g, 66% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 9.12 (s, 1H), 7.38 (m,7H), 7.11 (dd, J=7.2 & 3.2 Hz, 1H), 5.10 (s, 2H) and 4.90 (s, 2H) ppm.

6-Hydroxyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (H134)

H134 (13 mmol) was dissolved in MeOH (300 mL). To this solution undernitrogen was added 10% Pd/C (200 mg). The reaction mixture was vacuumedand backfilled hydrogen for 3 times, then stirred overnight at roomtemperature. After filtration and rotary evaporation, the residue waspurified by recrystallization to give the title compound (1.98 mg, 98%yield). ¹H NMR (300 MHz, DMSO-d₆): δ 9.29 (s, 1H), 9.04 (s, 1H), 7.18(d, J=8.4 Hz, 2H), 6.87 (dd, J=8.1 & 2.4 Hz, 1H) and 4.86 (s, 2H) ppm.Mp 133-135° C.

1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yl N-phenylcarbamate (H135)

6-Hydroxyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (0.667 mmol) wasdissolved in DMF (10 mL) and cooled to 0° C. with ice bath. To thissolution under nitrogen were added in sequence triethylamine (0.28 ml, 2mmol, 3.0 eq) and isocyanatobenzene (0.852 mL, 6.67 mmol, 10.0 eq). Thereaction mixture was stirred for 2 days at room temperature then treatedwith 1 M HCl (10 ml). After extraction with ethyl acetate, the organiclayer was washed with water and brine. The residue after rotaryevaporation was purified by column chromatography over silica gel togive the title compound (32 mg, 18% yield). ¹H NMR (300 MHz, DMSO-d₆): δ10.23 (s, 1H), 9.25 (s, 1H), 7.53-7.02 (m, 8H) and 5.00 (s, 2H) ppm.

1,3-Dihydro-1-hydroxy-2,1-benzoxaborol-6-yl N-cyclohexylcarbamate (H136)

6-Hydroxyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (0.667 mmol) wasdissolved in toluene (10 mL) and cooled to 0° C. with ice bath. To thissolution under nitrogen were added in sequence triethylamine (0.28 ml, 2mmol, 3.0 eq) and isocyanatocyclohexane (0.852 mL, 6.67 mmol, 10.0 eq).The reaction mixture was stirred for 2 days at room temperature thentreated with 1 M HCl (10 ml). The white solid was filtrated thenpurified by column chromatography over silica gel and recrystallizationto give the title compound (24 mg, 13% yield). ¹H NMR (300 MHz,Acetone-d₆): δ 8.09 (s, 1H), 7.42-7.37 (m, 2H), 7.19 (dd, J=8.4 & 2.1Hz, 1H), 6.65 (m, 1H), 5.00 (s, 2H), 3.46 (m, 1H) and 1.98-1.15 (m, 10H)ppm. Mp 198-200° C.

6-(2′-Fluoro)benzyloxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (H137)

6-Hydroxyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1 mmol) wasdissolved in DMF (10 mL) and cooled to 0° C. with ice bath. To thissolution under nitrogen were added in sequence sodium hydride (160 mg, 4mmol, 4.0 eq) and 1-(chloromethyl)-2-fluorobenzene (0.485 mL, 4 mmol,4.0 eq). The reaction mixture was stirred for 2 hours then treated with1 M HCl (10 ml). After extraction with ethyl acetate, the organic layerwas washed with water and brine. The residue after rotary evaporationwas purified by column chromatography over silica gel to give the titlecompound (143.6 mg, 55.7% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 9.13 (s,1H), 7.58-7.12 (m, 7H), 5.16 (s, 2H) and 4.92 (s, 2H) ppm. Mp 129-131°C.

6-(4′-Fluoro)benzyloxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (H138)

6-Hydroxyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1 mmol) wasdissolved in DMF (10 mL) and cooled to 0° C. with ice bath. To thissolution under nitrogen were added in sequence sodium hydride (160 mg, 4mmol, 4.0 eq) and 1-(chloromethyl)-4-fluorobenzene (0.485 mL, 4 mmol,4.0 eq). The reaction mixture was stirred for 2 hours then treated with1 M HCl (10 ml). After extraction with ethyl acetate, the organic layerwas washed with water and saturated brine. After rotary evaporation, theresidue was purified by column chromatography over silica gel to givethe title compound (228.2 mg, 88.4% yield). ¹H NMR (300 MHz, DMSO-d₆): δ9.13 (s, 1H), 7.53-7.11 (m, 7H), 5.10 (s, 2H) and 4.91 (s, 2H) ppm. Mp136-137° C.

6-(2-Nitrobenzyloxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (H139)

Compound 42 (200 mg, 1.33 mmol) was dissolved in DMF (9.0 mL) and cooledto 0° C. with ice bath. To this solution under nitrogen were added insequence NaH (60% in mineral oil, 133 mg, 3.33 mmol) and1-(bromomethyl)-2-nitrobenzene (432 mg, 2.00 mmol). The reaction mixturewas stirred for 1 h then treated with 1.0 M HCl (10.0 mL). Afterextraction with ethyl acetate, the organic phase was washed with waterand saturated brine. After rotary evaporation, the residue was purifiedby column chromatography over silica gel to give the title compound (153mg, 40% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.15 (d,J=7.2 Hz, 1H), 7.83-7.76 (m, 2H), 7.66-7.59 (m, 1H), 7.37-7.30 (m, 2H),7.15 (dd, J=8.1 & 2.4 Hz, 1H), 5.48 (s, 2H) and 4.92 (s, 2H) ppm; Mp:135-138° C.

6-(Benzyl)benzo[c][1,2]oxaborol-1(3H)-ol (H140)

Compound 22 (125 mg, 0.5 mmol) and NaBH₄ (190 mg, 5 mmol) was slowlyadded in portions with vigorous stirring to trifluoroacetic acid (20 mL)at 0° C. under nitrogen. After 15 min, aqueous NaHCO₃ was slowly addedand the solution was extracted with CH₂Cl₂. The organic layer was washedwith brine, dried over Na₂SO₄, and evaporated under vacuum to a solidresidue. The crude product was recrystallized from hexane and ethylacetate to give 105 mg of the product (90%).

6-Formyl-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (H141)

To a solution of compound 121 (24.0 g, 62.3 mmol) in THF (250 mL) undernitrogen at −78° C. was added dropwise n-BuLi solution (1.6M in hexane,42.9 mL, 68.6 mmol, 1.1 eq) over 30 minutes. After the mixture wasstirred at −78° C. for another 20 minutes, triisopropyl borate (15.7 mL,68.6 mmol, 1.1 eq) was added over 10 minutes. The mixture was allowed towarm to room temperature gradually and stirred overnight before quenchedwith 6M HCl (100 mL). The mixture was stirred for another 6 hours atroom temperature. All of solvents were evaporated under reduced pressureto give crude product 122 which was used to oxidative reaction withoutpurification.

To a mixture of crude product 122 in CH₂Cl₂ (250 mL) were added PCC(26.8 g, 124.6 mmol, 2.0 eq) and Celite (40.2 g). The mixture wasstirred overnight at room temperature. The reaction mixture was filteredthrough celite and silica gel pad and the filtrate was washed with 1 MHCl and 1 M NaOH. The aqueous phase was acidified by concentrated HCl topH 2 and extracted with ethyl acetate. The organic phase was washed withbrine, dried over anhydrous Na₂SO₄, and evaporated to give crude product(4.70 g) which was purified by column chromatography andrecrystallization to give the title compound (1.60 g, 15.8% yield). ¹HNMR (300 MHz, DMSO-d₆): δ 10.06 (s, 1H), 9.44 (s, 1H), 8.28 (s, 1H),8.01 (m, 1H), 7.63 (m, 1H) and 5.09 (s, 2H) ppm. Mp 133-135° C.

7-Formyl-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (H142)

H142 can be synthesized using the following procedure:

6-(4-Nitro-phenylsulfanyl)-3H-benzo[c][1,2]oxaborol-1-ol (H143)

To a solution of 4-nitro-benzenethiol (3.1 g, 20.0 mmol, 1.0 eq.),2-bromo-4-fluoro-benzaldehyde (4.1 g, 20.0 mmol, 1.0 eq.) in DMF (40.0mL) was added K₂CO₃ (5.5 g, 40.0 mmol, 2.0 eq.) under nitrogenatmosphere. The mixture was heated at 100° C. overnight. After coolingto room temperature, the mixture was filtered through a short pack ofcelite to remove the solid residue. The filtrate was concentrated underreduced pressure to ⅕ volume and poured into DCM (30 mL) and H₂O (30mL). The aqueous phase as slightly acidified by adding a couple drop ofHCl (3N) and the layers were separated and the aqueous phase wasextracted with DCM (3×30 mL). Combined organic extracts was washed withbrine (30 mL), dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. The residue was applied to silicachromatography eluting with EtOAc/heptanes (0:100 to 100:0) to give2-bromo-4-(4-nitro-phenylsulfanyl)-benzaldehyde as a fine yellow powder.¹H NMR(CHLOROFORM-d) δ: 10.35 (s, 1H), 8.43 (dd, J=2.3, 0.6 Hz, 1H),7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.69-7.77 (m, 2H), 7.30 (dd, J=8.6, 3.0Hz, 1H), 7.12 (dd, J=8.6, 0.8 Hz, 1H). Amount obtained, 4.3, 71.2%yield.

To a solution of 2-bromo-4-(4-nitro-phenylsulfanyl)-benzaldehyde (2.7 g,8.0 mmol, 1.0 eq.) in 1,4-dioxane (50 mL) was added bis-pinacol-diboron(2.23 g, 8.8 mmol, 1.1 eq.), KOAc (2.35 g, 24.0 mmol, 3.0 eq.) andPdCl₂(dppf)₂ (175 mg, 0.24 mmol, 0.03 eq.). The mixture was degassedwith N₂ and heated at 80° C. overnight. After cooling to roomtemperature, the mixture was filtered though a short pack of celite andthe filtrate was concentrated under reduced pressure. The residue wasapplied to silica chromatography eluting with EtOAc/Heptanes (0:100 to50:50) to give4-(4-nitro-phenylsulfanyl)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehydeas a yellow solid. ¹H NMR(CHLOROFORM-d) δ: 10.56 (s, 1H), 8.20-8.25 (m,2H), 8.11-8.17 (m, 1H), 7.94-8.00 (m, 2H), 7.47-7.53 (m, 1H), 7.33-7.38(m, 1H), 1.27 (s, 12H).

To a suspension of4-(4-nitro-phenylsulfanyl)-2-(4,4,5,5-tetramethyl-1,3,2]dioxaborolan-2-yl)-benzaldehyde(1.3 g, 3.4 mmol, 1.0 eq.) in EtOH (30 mL) at 0° C. was added NaBH₄(127.7 mg, 3.4 mmol, 1.0 eq.) in small portions. The mixture was stirredat 0° C. for 20 minutes and allowed to warm to room temperature inanother 1 h. After cooling to 0° C., the clear solution was carefullytreated with H₂O (1 mL), followed by slow addition of HCl (10 mL, 3N).The resulting yellow suspension was allowed to ward to room temperaturegradually and stirred for 2 h. The mixture was then treated with sat.NaHCO₃ drop wise until PH reaching 7. The precipitate was collected byfiltration and applied to silica chromatography eluting with MeOH/DCM(0:100 to 10:90) to give6-(4-nitro-phenylsulfanyl)-3H-benzo[c][1,2]oxaborol-1-ol as a whitesolid. LCMS (m/z) 310 (M+23); ¹H NMR (DMSO-d₆) δ: 9.32 (s, 1H),8.08-8.14 (m, 2H), 7.91 (d, J=1.2 Hz, 1H), 7.67 (dd, J=7.9, 1.8 Hz, 1H),7.57 (dd, J=7.9, 0.6 Hz, 1H), 7.22-7.28 (m, 2H), 5.05 (s, 2H).

6-(Pyridin-4-ylsulfanyl)-3H-benzo[c][1,2]oxaborol-1-ol (H144)

H144 was prepared using a procedure similar to compound H143 bysubstituting 4-nitro-benzenethiol with 4-mercaptopyridine. LCMS (m/z)244 (M+H); ¹H NMR (DMSO-d₆) δ: 9.32 (s, 1H), 8.34 (d, J=6.0 Hz, 2H),7.91 (s, 1H), 7.66 (d, J=9.3 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 6.98 (d,J=6.0 Hz, 2H), 5.05 (s, 2H).

6-(3-Methoxy-phenylsulfanyl)-3H-benzo[c][1,2]oxaborol-1-ol (H145)

H145 was prepared using a procedure similar to compound H143 bysubstituting 4-nitrobenzenethiol with 3-methoxybenzenethiol. LCMS (m/z)273 (M+H); ¹H NMR (DMSO-d₆) δ: 9.24 (s, 1H), 7.74 (d, J=1.2 Hz, 1H),7.46-7.51 (m, 1H), 7.40-7.46 (m, 1H), 7.25 (t, J=8.2 Hz, 1H), 6.82 (ddd,J=8.2, 2.4, 0.9 Hz, 1H), 6.75-6.80 (m, 2H), 4.98 (s, 2H), 3.69 (s, 3H).

2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfanyl)-benzoicacid methyl ester (H146)

H146 was prepared using a procedure similar to compound H143 bysubstituting 4-nitrobenzenethiol with methyl thiosalicylate. LCMS (m/z)323 (M+23); ¹H NMR (DMSO-d₆) δ: 9.29 (s, 1H), 7.90 (dd, J=7.8, 1.5 Hz,1H), 7.86 (d, J=1.2 Hz, 1H), 7.58-7.64 (m, 1H), 7.50-7.57 (m, 1H), 7.38(td, J=7.7, 1.6 Hz, 1H), 7.22 (td, J=7.6, 1.1 Hz, 1H), 6.73 (dd, J=8.1,0.8 Hz, 1H), 5.04 (s, 2H), 3.86 (s, 3H).

6-(3-Methoxy-benzenesulfinyl)-3H-benzo[c][1,2]oxaborol-1-ol (H147)

To a 20 mL scintillation vial containing6-(3-methoxy-phenylsulfanyl)-3H-benzo[c][1,2]oxaborol-1-ol (200 mg, 0.73mmol, 1.0 in MeOH (9.0 mL) was added a solution of NaIO₄ (172.9 mg, 0.81mmol, 1.1 eq.) in H₂O (1.0 mL. The mixture was stirred at roomtemperature overnight. The mixture was treated with H₂O (10 mL) and wasextracted with EtOAc (3×10 mL), combined organic phase was washed withbrine (10 mL), dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. The residue was applied to silicachromatography eluting with MeOH/DCM (0:100 to 10:90) to give6-(3-methoxy-benzenesulfinyl)-3H-benzo[c][1,2]oxaborol-1-ol as a whitesolid. LCMS (m/z) 289 (M+H); ¹H NMR (DMSO-d₆) δ: 9.35 (s, 1H), 8.07 (d,J=1.1 Hz, 1H), 7.79 (dd, J=8.0, 1.8 Hz, 1H), 7.53 (dd, J=8.0, 0.6 Hz,1H), 7.42 (t, J=8.0 Hz, 1H), 7.18-7.28 (m, 2H), 6.99-7.05 (m, 1H), 4.98(s, 2H), 3.76 (s, 3H).

6-(4-Amino-phenylsulfanyl)-3H-benzo[c][1,2]oxaborol-1-ol (H148)

To a 25 mL round-bottom flask fitted with magnetic stirring bar wasadded 4-nitro-phenylsulfanyl)-3H-benzo[c][1,2]oxaborol-1-ol (120 mg,0.42 mmol, 1.0 eq.), followed by addition of EtOH (4 mL) and THF (1 mL).The flask was evacuated and recharged with N₂ twice. To the stirringsolution was added 5% Pd/C (20 mg) and the flask was evacuated andrecharged with H₂ three times. The resulting suspension was stirredunder a H₂ balloon at room temperature overnight. The mixture wasfiltered through a short pack of celite and washed with MeOH (3×10 mL).The combined filtrate was concentrated under reduced pressure to give awhite solid. The solid was dissolved in minimum amount of MeOH andcarefully treated with HCl (conc.). The precipitate was collected byfiltration, washed with heptanes to give6-(4-amino-phenylsulfanyl)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloridesalt as a white solid. LCMS (m/z) 258 (M+H); ¹H NMR (DMSO-d₆) δ: 7.72(d, J=3.9 Hz, 1H), 7.40-7.48 (m, 2H), 7.27-7.32 (m, 2H), 7.21 (t, J=8.8Hz, 2H), 4.97 (s, 2H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfanyl)-phenyl]-benzamide(H149)

To a 20 mL scintillation vial containing6-(4-amino-phenylsulfanyl)-3H-benzo[c][1,2]oxaborol-1-ol (77.1 mg, 0.3mmol, 1.0 eq.) in DCM (4.0 mL) was added Et₃N (58.5 μL, 0.42 mmol, 1.4eq.), followed by benzoyl chloride (42.7 μL, 0.36 mmol, 1.2 eq.). Theresulting white suspension was diluted with DCM (5 mL). The precipitatewas collected by filtration and washed with DCM to giveN-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfanyl)-phenyl]-benzamideas a white solid. LCMS (m/z) 362 (M+H); ¹H NMR (DMSO-d₆) δ: 10.36 (s,1H), 9.21 (s, 1H), 7.93 (d, J=7.0 Hz, 2H), 7.81 (t, J=4.7 Hz, 1H), 7.81(d, J=8.7 Hz, 1H), 7.62 (s, 1H), 7.55-7.61 (m, 1H), 7.48-7.55 (m, 1H),7.52 (d, J=7.7 Hz, 1H), 7.33-7.43 (m, 4H), 4.96 (s, 2H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfanyl)-phenyl]-2-trifluoromethyl-benzamide(H150)

H150 was prepared using a procedure similar to that of H149 bysubstituting benzoyl chloride with 2-trifluoromethylbenzoyl chloride.LCMS (m/z) 452 (M+23); ¹H NMR (DMSO-d₆) δ: 10.68 (s, 1H), 9.22 (s, 1H),7.83 (d, J=7.9 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.66-7.73 (m, 4H), 7.63(s, 1H), 7.35-7.42 (m, 4H), 4.96 (s, 2H).

Cyclohexanecarboxylic acid[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfanyl)-phenyl]-amide(H151)

H151 was prepared using a procedure similar to that of H149 bysubstituting benzoyl chloride with cyclohexanecarbonyl chloride. LCMS(m/z) 390 (M+23); ¹H NMR (DMSO-d₆) δ: 9.92 (s, 1H), 9.19 (s, 1H), 7.63(d, J=8.7 Hz, 1H), 7.63 (q, J=4.6 Hz, 1H), 7.56 (s, 1H), 7.29-7.38 (m,4H), 4.94 (s, 2H), 2.30 (t, J=2.7 Hz, 1H), 2.25-2.35 (m, 1H), 1.75 (t,J=13.7 Hz, 4H), 1.59-1.66 (m, 1H), 1.38 (d, J=11.9 Hz, 1H), 1.31-1.44(m, 1H), 1.23 (quin, J=12.4 Hz, 2H), 1.11-1.31 (m, 1H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfanyl)-phenyl]-acetamide(H152)

H152 was prepared using a procedure similar to that of H149 bysubstituting benzoyl chloride with acetyl chloride. LCMS (m/z) 300(M+H); ¹H NMR (DMSO-d₆) δ: 10.05 (s, 1H), 7.55-7.59 (m, 3H), 7.28-7.38(m, 4H), 4.94 (s, 2H), 2.02 (s, 3H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfanyl)-phenyl]-4-methoxy-benzamide(H153)

H153 was prepared using a procedure similar to that of H149 bysubstituting benzoyl chloride with 4-methoxybenzoyl chloride. LCMS (m/z)392 (M+H); ¹H NMR (DMSO-d₆) δ: 10.19 (s, 1H), 9.21 (s, 1H), 7.90-7.97(m, 2H), 7.77-7.83 (m, 2H), 7.62 (s, 1H), 7.32-7.41 (m, 4H), 7.01-7.08(m, 2H), 4.95 (s, 2H), 3.82 (s, 3H).

4-Chloro-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfanyl)-phenyl]-benzamide(H154)

H154 was prepared using a procedure similar to that of H149 bysubstituting benzoyl chloride with 4-chlorobenzoyl chloride. LCMS (m/z)418 (M+23); ¹H NMR (DMSO-d₆ δ: 10.41 (s, 1H), 9.21 (s, 1H), 7.96 (d,J=8.6 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.57-7.62 (m, 3H), 7.33-7.42 (m,4H), 4.96 (s, 2H).

H155

This compound was prepared using a procedure similar to that of H104 bysubstituting 3-chlorophenyl sulfide with 4-isopropylphenyl sulfide. ¹HNMR (400 MHz, DMSO-d₆): δ 9.26 (s, 1H), 7.70 (d, J=0.8 Hz, 1H), 7.43 (m,2H), 7.25 (s, 4H), 4.98 (s, 2H), 2.85 (m, 1H), 1.19 (s, 3H) and 1.17 (s,3H) ppm.

Example 2 Trypanosoma brucei brucei High-Throughput Screening AssayProcedure

Experiments were conducted with the bloodstream-form trypanosome T.brucei brucei S427 strain and the T. brucei brucei STIB 795 strain.Parasites were cultured in T-25 vented cap flasks and kept in humidifiedincubators at 37° C. and 5% CO₂. The parasite culture media was completeHMI-9 medium (c.f. Hirumi, Journal of Parasitology, 40:75, 985-989(1989)) containing 10% FBS, 10% Serum Plus medium andpenicillin/streptomycin. To ensure log growth phase, trypanosomes weresub-cultured at appropriate dilutions every 2-3 days.

In Vitro Drug Sensitivity Assays

Log phase cultures were diluted 1:10 in HMI-9 and 10 uL was countedusing hemocytometer to determine parasite concentration. Parasites werediluted to 2×10⁵/mL in HMI-9 to generate a 2-fold working concentrationfor assay. Compounds to be tested were serially diluted in DMSO and 0.5uL added to 49.5 uL HMI-9 in triplicate 96-well plates using a Biomek NXliquid handler. Parasites from the diluted stock were added to each well(50 uL) using a Multidrop 384 dispenser to give a final concentration of1.0×10⁵/ml parasites in 0.4% for DMSO. Trypanosomes were incubated withcompounds for 72 hrs at 37° C. with 5% CO₂. Resazurin (20 uL of 12.5mg/ml stock) from Sigma-Aldrich was added to each well and plates wereincubated for an additional 2-4 hrs. Assay plates were read using anEnVision plate reader at an excitation wavelength of 544 nm and emissionof 590 nm. Triplicate data points were averaged to generate sigmoidaldose response curve and determine IC₅₀ values using XLfit curve fittingsoftware from IDBS (Guildford, UK).

Results from the S427 strain and the STIB 795 strain are provided inFIG. 1.

Example 3 Trypanosoma cruzi C2C4 Screening Assay Procedure

Rat skeletal myoblasts (L-6 cells) were seeded in 96-well microtitreplates at 2×10³ cells/well in 100 μL RPMI 1640 medium with 10% FBS and 2mM L-glutamine. After 24 h the medium was removed and replaced by 100 μlper well containing 5×10³ trypomastigote forms of T. cruzi Tulahuenstrain C2C4 containing the β-galactosidase (Lac Z) gene (Buckner, etal., Antimicrobial Agents and Chemotherapy, 40: 2592-2597 (1996)). After48 h the medium was removed from the wells and replaced by 100 μl freshmedium with or without a serial drug dilution of seven 3-fold dilutionsteps covering a range from 90 to 0.123 μg/ml. After 96 h of incubationthe plates were inspected under an inverted microscope to assure growthof the controls and sterility. The substrate (50 μl) chlorophenolred-β-D-galactopyranoside (CPRG, Roche Diagnostics Ltd) in 0.25% NonidetP-40/PBS was added to all wells and a color reaction developed within2-6 h. which was read photometrically at 540 nm. Data were transferredinto the graphic programme Softmax Pro (Molecular Devices), whichcalculated IC50 values.

Results from this assay are provided in FIG. 1.

Example 4 Trypanosoma cruzi CL2 Screening Assay Procedure

Parasite and cell cultures. Trypanosoma cruzi, Tulahuen CL2, βgalactosidase strain (nifurtimox-sensitive) was used (Buckner et al.,Antimicrob Agents Chemother. 40: 2592-2597 (1996)). The strain wasmaintained in MRC-5SV2 (human lung fibroblast) cells. A SV-40transformed cell line was available to obtain unlimited subcultivationcharacteristics in MEM medium, supplemented with 200 mM. L-glutamine,16.5 mM NaHCO₃, and 5% inactivated fetal calf serum. All cultures andassays were conducted at 37° C. with 5% CO₂.

Compound Solutions/Dilutions.

Compound stock solutions were prepared in 100% DMSO at 20 mM or mg/mlfor natural products, drug mixtures and if the molecular weight was notknown. The compounds were serially pre-diluted (2-fold or 4-fold) inDMSO followed by a further (intermediate) dilution in demineralizedwater to assure a final in-test DMSO concentration of <1%.

Drug Sensitivity Assays.

Assays were performed in sterile 96-well microtiter plates, each wellcontaining 10 μl of the watery compound dilutions together with 190 μlof MRC-5 cell/parasite inoculum (4×10³ cells/well+4×10⁴ parasites/well).Parasite growth was compared to untreated-infected controls (100%growth) and noninfected controls (0% growth) after 7 days incubation at37° C. and 5% CO₂. Parasite burdens were assessed after adding thesubstrate CPRG (chlorophenolred β-D-galactopyranoside): 50 μl/well of astock solution containing 15.2 mg CPRG+250 μl Nonidet in 100 ml PBS. Thechange in color was measured spectrophotometrically at 540 nm after 4hours incubation at 37° C. The results were expressed as % reduction inparasite burdens compared to control wells and an 1050 (50% inhibitoryconcentration) was calculated.

Primary Screen.

Trypanosoma cruzi β galactosidase strain was used. Compounds were testedat 5 concentrations (64-16-4-1 and 0.25 μM or ug/ml). Nifurtimox orbenznidazole were included as the reference drugs. The test compound wasclassified as inactive when the IC₅₀ was higher than 30 μM. When theIC50 was between 30 and 5 μM, the compound was regarded as beingmoderate active. When the IC₅₀ was lower than 5 μM, the compound wasclassified as highly active on the condition that it also demonstratedselective action (absence of cytotoxicity). A final recommendation foractivity was given after confirmatory evaluation in a secondaryscreening.

Secondary Screen.

Trypanosoma cruzi β galactosidase strain was used and IC50-values weredetermined using an extended dose range (2-fold compound dilutions).Nifurtimox or benznidazole was included as reference drugs. Advancedselectivity evaluation was performed against a panel of unrelatedorganisms (bacteria, yeasts, fungi and other protozoan parasites).

Results from this assay are provided in FIG. 1.

Example 5 Trypanosoma brucei gambiense Screening Assay Procedure

The following T. b. gambiense strains were isolated from sleepingsickness patients as described, and were subsequently propagated in miceat Swiss Tropical Institute.

-   -   T. b. gambiense 40R, 108R were isolated by Pati Pyana in Mbuji        Mayi (D.R Congo) in 2005 and then propagated in STI (Swiss        Tropical Institute, Basel, Switzerland) in different mice in        winter 2006.        -   40R is a relapse 6 months after a 10 days melarsoprol            treatment.        -   108R is a relapse 8 months after a 10 days melarsoprol            treatment    -   T. b. gambiense DAL 1402 was obtained from the cryobank of the        “Project de Recherches Cliniques Sur la Trypanosomiase,” in        Daloa. It was isolated in 1990 from a human patient in Cote        d'Ivoire.    -   T. b. gambiense ITMAP 141267 was isolated in Bandundu/Lac        Mai-Ndombe, DRC, 1960    -   T. b. gambiense Drani was isolated from a patient in Uganda;        West Nile, 1995; original stabilate ID: UTRO 210396 A.

In Vitro Culture and Assay Procedure:

50 μl HMI-9 medium (Hirumi et al., J. Parasitology, 75: 985-989 (1989))supplemented 10% heat inactivated fetal calf serum and 5% heatinactivated human serum was added to each well of a 96-well microtiterplate. Serial drug dilutions of seven 3-fold dilution steps covering arange from 90 to 0.123 μg/ml were prepared. Then 2×10⁵ bloodstream formsof T. b. gambiense in 50 μl medium was added to each well and the plateincubated at 37° C. under a 5% CO₂ atmosphere for 72 h. 10 μl AlamarBlue (resazurin, 12.5 mg in 100 ml double-distilled water) was thenadded to each well and incubation continued for a further 2-4 h (Räz etal, Acta Trop 68:139-47 (1997)). Then the plates were read with aSpectramax Gemini XS microplate fluorometer (Molecular DevicesCooperation, Sunnyvale, Calif., USA) using an excitation wave length of536 nm and an emission wave length of 588 nm. Data were analyzed usingthe microplate reader software Softmax Pro (Molecular DevicesCooperation, Sunnyvale, Calif., USA).

Results from the 108R, 40R, DAL1402, DRANI, and ITMAP strains areprovided in FIG. 1.

Example 6 Trypanosoma brucei rhodesiense STIB 900 Screening AssayProcedure

The Trypanosoma brucei rhodesiense STIB900 strain was isolated in 1982from a human patient in Tanzania and after several mouse passages clonedand adapted to axenic culture conditions (Baltz, et al., EMBO Journal4:1273-1277 (1985); Thuita, et al., Acta Tropica 108:6-10 (2008)).Minimum Essential Medium (50 μl) supplemented with 25 mM HEPES, 1 g/Ladditional glucose, 1% MEM non-essential amino acids (100×), 0.2 mM2-mercaptoethanol, 1 mM Na-pyruvate and 15% heat inactivated horse serumwas added to each well of a 96-well microtiter plate. Serial drugdilutions of seven 3-fold dilution steps covering a range from 90 to0.123 μg/ml were prepared. Then 10⁴ bloodstream forms of T. b.rhodesiense STIB 900 in 50 μl was added to each well and the plateincubated at 37° C. under a 5% CO₂ atmosphere for 72 h. 10 μl AlamarBlue (resazurin, 12.5 mg in 100 ml double-distilled water) was thenadded to each well and incubation continued for a further 2-4 h (Räz, etal., Acta Trop 68:139-47 (1997)). Then the plates were read with aSpectramax Gemini XS microplate fluorometer (Molecular DevicesCooperation, Sunnyvale, Calif., USA) using an excitation wave length of536 nm and an emission wave length of 588 nm. Data were analyzed usingthe microplate reader software Softmax Pro (Molecular DevicesCooperation, Sunnyvale, Calif., USA).

Results from this assay are provided in FIG. 1.

Example 7 Leishmania donovani Axenic Amastigote Screening AssayProcedure

Amastigotes of L. donovani strain MHOM/ET/67/L82 were grown in axenicculture at 37° C. in SM medium (Cunningham, I. J Protozol. 24:325-329(1977)) at pH 5.4 supplemented with 10% heat-inactivated fetal bovineserum under an atmosphere of 5% CO₂ in air. One hundred microliters ofculture medium with 10⁵ amastigotes from axenic culture with or withouta serial drug dilution were seeded in 96-well microtitre plates. Serialdrug dilutions of seven 3-fold dilution steps covering a range from 90to 0.123 μg/ml were prepared. After 72 h of incubation the plates wereinspected under an inverted microscope to assure growth of the controlsand sterile conditions. 10 μl of Alamar Blue (12.5 mg resazurindissolved in 100 ml distilled water) (Mikus and Steverdig, ParasitologyInternational 48:265-269 (2000)) were then added to each well and theplates incubated for another 2 h. Then the plates were read with aSpectramax Gemini XS microplate fluorometer (Molecular DevicesCooperation, Sunnyvale, Calif., USA) using an excitation wave length of536 nm and an emission wave length of 588 nm. Data were analyzed usingthe software Softmax Pro (Molecular Devices Cooperation, Sunnyvale,Calif., USA). Decrease of fluorescence (=inhibition) was expressed aspercentage of the fluorescence of control cultures and plotted againstthe drug concentrations. From the sigmoidal inhibition curves the IC₅₀values were calculated.

Example 8 Leishmania donovani Macrophage and Leishmania infantumMacrophage Screening Assay Procedure

Parasite and cell cultures. Two Leishmania species (L. infantumMHOM/MA(BE)/67 and L. donovani MHOM/ET/67/L82) were used. The strainswere maintained in the Golden Hamster (Mesocricetus auratus).Amastigotes were collected from the spleen of an infected donor hamsterusing three centrifugation purification steps (300 rpm, keeping thesupernatant, 2200 rpm, keeping the supernatants and 3500 rpm, keepingthe pellet) and spleen parasite burdens were assessed using the Staubertechnique (Stauber L A., Exp Parasitol. 18: 1-11 (1966)). Primaryperitoneal mouse macrophages were used as host cell and were collected 2days after peritoneal stimulation with a 2% potato starch suspension.All cultures and assays were conducted at 37° C. under an atmosphere of5% CO₂.

Compound Solutions/Dilutions.

Compound stock solutions were prepared in 100% DMSO at 20 mM or mg/ml.Concentrations were standard and expressed in molar concentrations,except for natural products, drug mixtures and if the molecular weightwas not known. The compounds were serially pre-diluted (2-fold or4-fold) in DMSO followed by a further (intermediate) dilution indemineralized water to assure a final in-test DMSO concentration of <1%.

Drug Sensitivity Assays.

Assays were performed in 96-well microtiter plates, each well contained10 μl of the compound dilutions together with 190 μl ofmacrophage/parasite inoculum (3×10³ cells+4.5×10⁵ parasites/well). Theinoculum was prepared in RPMI-1640 medium, supplemented with 200 mML-glutamine, 16.5 mM NaHCO₃, and 5% heat-inactivated fetal calf serum.Parasite multiplication was compared to untreated-infected controls(100% growth) and uninfected controls (0% growth). After 5 daysincubation, parasite burdens (mean number of amastigotes/macrophage)were microscopically assessed after staining the cells with a 10% Giemsasolution. The results were expressed as % reduction in parasite burdencompared to untreated control wells and an IC₅₀ (50% inhibitoryconcentration) was calculated.

Primary Screen.

Leishmania infantum MHOM/MA(BE)/67 strain was used. The compounds weretested at 5 concentrations (64-16-4-1 and 0.25 μM or μg/ml).Sodium-stibogluconate (IC₅₀=8.7+2.1 μM) and miltefosin (IC₅₀=4.3+1.1 μM)were included as the reference drugs. A test compound was classified asinactive when the IC₅₀ was higher than 30 μM. When the IC₅₀ was between30 and 10 μM, the compound was regarded as moderately active. If theIC₅₀ is lower than 10 μM, the compound was classified as highly activeon the condition that it also demonstrates selective action (absence ofcytotoxicity against primary peritoneal macrophages). A finalrecommendation for activity was given after confirmatory evaluation in asecondary screening.

Secondary Screen.

Leishmania infantum MHOM/MA(BE)/67 and L. donovani MHOM/ET/67/L82strains were used and the IC₅₀-values were determined using an extendeddose range (2-fold compound dilutions). Pentostam®, miltefosine,fungizone and PX-6518 were included as reference drugs. Advancedselectivity evaluations were performed against a panel of unrelatedorganisms (bacteria, yeasts, fungi and other protozoan parasites).

Results from this assay are provided in FIG. 1.

Example 9 Plasmodium falciparum Screening Assay Procedure

In vitro activity against erythrocytic stages of P. falciparum wasdetermined using a ³H-hypoxanthine incorporation assay (Desjardins etal., Antimicrobial Agents and Chemotherapy 16:710-718 (1979), Matiel andPink. Plasmodium falciparum malaria parasite cultures and their use inimmunology. In I. Lefkovits and B. Pernis (ed.), Immunological Methods.Academic Press, San Diego (1990)), using the chloroquine andpyrimethamine resistant K1 strain that originate from Thailand (Thaitonget al. Transactions of the Royal Society of Tropical Medicine andHygiene 77:228-231 (1983)) and the standard drug chloroquine (SigmaC6628). Compounds were dissolved in DMSO at 10 mg/ml and added toparasite cultures incubated in RPMI 1640 medium without hypoxanthine,supplemented with HEPES (5.94 g/l), NaHCO₃ (2.1 g/l), neomycin (100U/ml), Albumax^(R) (5 g/l) and washed human red cells A⁺ at 2.5%haematocrit (0.3% parasitaemia). Serial drug dilutions of seven 2-folddilution steps covering a range from 5 to 0.156 μg/ml were prepared. The96-well plates were incubated in a humidified atmosphere at 37 C; 4%CO₂, 3% O₂, 93% N₂. After 48 h 50 μl of ³H-hypoxanthine (=0.5 μCi) wasadded to each well of the plate. The plates were incubated for a further24 h under the same conditions. The plates were then harvested with aBetaplate™ cell harvester (Wallac, Zurich, Switzerland), and the redblood cells transferred onto a glass fibre filter then washed withdistilled water. The dried filters were inserted into a plastic foilwith 10 ml of scintillation fluid, and counted in a Betaplate™ liquidscintillation counter (Wallac, Zurich, Switzerland). IC₅₀ values werecalculated from sigmoidal inhibition curves using Microsoft Excel.

Results from this assay are provided in FIG. 1.

Example 10 In vitro Trypanosoma PDE assays

A solution can be formed including a compound described herein, 40 mMMops, pH 7.5, 0.8 mM EGTA, 15 mM magnesium acetate, 0.2 mg/ml bovineserum albumin (BSA) and 100000 c.p.m. of [³H]cAMP, in a final volume of250 μl at 30° C. The assay reaction can be started with the addition ofthe trypanosoma PDE (the amount will be in the linear hydrolysis vs.time zone as determined in a preliminary experiment) to this mixture. Ifthe trypanosoma PDE source is a cell lysate or protein homogenate, thenan inhibitor of endogenous PDEs, such as, but not limited to, IBMX(3-isobutylmethylxanthine), may be added. The reaction can be terminatedby boiling the mixture for 2 minutes and the resulting AMP can beconverted to adenosine by the addition of 10 mg/ml snake venomnucleotidase and further incubation at 37° C. for 10 minutes.Unhydrolyzed cAMP can be bound to AG1-X2 resin, and the remaining[³H]Adenosine in the aqueous phase can be quantitated by scintillationcounting. Compounds described herein can be tested at concentrationsvarying from 0.001 to 100 μM for IC₅₀ determination. Trypanosoma bruceiPDEA (TbrPDEA, formerly known as TbPDE1) can be obtained through themethods described in Kunz, et al., Eur. J. Biochem. 271: 637-647 (2004).Trypanosoma brucei PDEB1 (TbrPDEB1, formerly known as TbPDE2C) can beobtained through the methods described in Zoraghi, et al., Proc. Natl.Acad. Sci. U.S.A. 99: 4343-4348 (2002). Trypanosoma brucei PDEB2(TbrPDEB2, formerly known as TbPDE2B) can be obtained through themethods described in Rascon, et al., Proc. Natl. Acad. Sci. U.S.A. 99:4714-4719 (2002). Trypanosoma brucei PDE2A (TbPDE2A) can be obtainedthrough the methods described in Zoraghi, et al., J. Biol. Chem., 276:11559-11566 (2001).

Example 11 Acute Murine Model A

Female Swiss Webster mice were inoculated with 250,000 parasites of theLAB 110 EATRO strain of T. b. brucei. 24 hrs post-infection, treatmentwas initiated BID for 4 days with 20 mg/kg/dose (40 mg/kg/day)intraperitoneally (IP) or orally (PO), 5 mg/kg BID or 10 mg/kg BIDorally (PO). N=3 mice/group. Mice were monitored for 30 days forsurvival. Pentamidine at 2 mg/kg IP was used as the positive control.After 10 days, 0% of the untreated mice were parasite free. After 10days, 100% of mice treated with 20 mg/kg, ip, BID of6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol were parasitefree. After 30 days, 100% of mice treated with 10 mg/kg, ip, BID ofN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamidewere parasite free. These results indicate thatN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,2-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide,5-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamideand4-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamidecan prevent the development of diseases associated with T. b. brucei.These results indicate thatN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide,2-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide,5-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamideand4-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamidehas potential for development to treat early-stage HAT.

T. brucei Compound Route Minimum Effective Dose H1 ip 10 mg/kg, bid × 4days H7 po 10 mg/kg, bid × 4 days H17 po  5 mg/kg, bid × 4 days H19 po 5 mg/kg, bid × 4 daysAcute Murine Model B

Female BALB/C mice were inoculated with 600 parasites of T. b. brucei or10⁴ parasites of T. b. rhodesiense. 24 hrs post-infection, treatmentwith 6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol wasinitiated BID for 5 days at 50 mg/kg BID intraperitoneally (IP). Micewere monitored for 40-60 days for survival. After 10 days, 20% of theuntreated mice were parasite free and at 20 days, 0% of the untreatedmice were parasite free. After 55 days, 100% of mice treated with6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol were parasitefree. These results indicate that6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1(3H)-ol can prevent thedevelopment of diseases associated with T. b. brucei or T. b.rhodesiense.

Example 12 Chronic CNS Model

Mice were infected with 10,000 parasites of the TREU 667 strain of T. b.brucei. Twenty one days post-infection mice were treated with 50 mg/kgof the compound BID for 7 days intraperitoneally (IP). Positive controlmice were treated with Berenil on Day 4 post-infection. Negative controlmice were treated with Berenil on Day 21. Since Berenil is not able topenetrate the CNS, mice treated at Day 21 are not able to cure theinfection. Starting 1 week after the end of treatment, mice aremonitored for parasitemia and sacrificed if parasites are detected inthe blood. Mice that survive 6 months are considered “cured.”

Treatment with 50 mg/kg ofN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamideBID for 7 days, starting at Day 21 post-infection, resulted in absenceof blood parasites through Day 91 in 70% of the mice. In contrast, allanimals treated on Day 21 with the non-CNS penetrant drug Diminazenerelapsed to exhibit blood parasitemia by Day 53. These results indicatethatN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamidehas potential for development to treat late-stage HAT.

Additional Results: 100% of mice treated with H17 were parasite free forat least 60 days. 100% of mice treated with H7 or H19 were parasite freefor at least 100 days.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound, or a salt thereof, having a structureaccording to the following formula:

wherein R* is H or negative charge; and X is selected from the groupconsisting of substituted phenyl, unsubstituted heteroaryl, substitutedheteroaryl, and unsubstituted cycloalkyl; wherein said substitutedphenyl is phenyl, substituted with at least one member selected from thegroup consisting of halogen, cyano, nitro, OR, SR, NRR, unsubstitutedalkyl, substituted alkyl, unsubstituted heteroalkyl, substitutedheteroalkyl, unsubstituted cycloalkyl, substituted cycloalkyl,unsubstituted heterocycloalkyl, substituted heterocycloalkyl,unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, andsubstituted heteroaryl, wherein each R is independently selected fromthe group consisting of unsubstituted alkyl, substituted alkyl,unsubstituted heteroalkyl, substituted heteroalkyl, unsubstitutedcycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl,substituted heterocycloalkyl, unsubstituted aryl, substituted aryl,unsubstituted heteroaryl, and substituted heteroaryl.
 2. The compound ofclaim 1, or a salt thereof, wherein X is phenyl, substituted with atleast one member selected from the group consisting of: halogen, cyano,nitro, OR, SR, NRR, unsubstituted alkyl, substituted alkyl,unsubstituted heteroalkyl, substituted heteroalkyl, unsubstitutedcycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl,substituted heterocycloalkyl, unsubstituted aryl, substituted aryl,unsubstituted heteroaryl, and substituted heteroaryl, wherein each R isindependently selected from the group consisting of unsubstituted alkyl,substituted alkyl, unsubstituted heteroalkyl, substituted heteroalkyl,unsubstituted cycloalkyl, substituted cycloalkyl, unsubstitutedheterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl,substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl.3. The compound of claim 1, or a salt thereof, having a structureaccording to the following formula:

wherein Y¹ is a halogen; Y is halo-substituted C₁-C₆ alkyl.
 4. Thecompound of claim 3, or a salt thereof, wherein said Y¹ is a halogen,and said halogen is fluoro.
 5. The compound of claim 3, or a saltthereof, wherein said Y is halo-substituted C₁-C₆ alkyl, and saidhalo-substituted C₁-C₆ alkyl is trifluoromethyl.
 6. The compound ofclaim 3, or a salt thereof, having a structure according to thefollowing formula:


7. The compound of claim 3, or a salt thereof, having a structureaccording to the following formula:


8. The compound of claim 3, or a salt thereof, having a structureaccording to the following formula:


9. A combination comprising the compound of claim 1, or a salt thereof,together with at least one other therapeutically active agent.
 10. Apharmaceutical formulation comprising: a) the compound of claim 1, or apharmaceutically acceptable salt thereof; and b) a pharmaceuticallyacceptable excipient.
 11. The pharmaceutical formulation of claim 10,wherein the pharmaceutical formulation is a unit dosage form.
 12. Thecompound of claim 1, wherein the salt of said compound is apharmaceutically acceptable salt.
 13. A method of killing and/orinhibiting the growth of a protozoa, comprising: contacting the protozoawith an effective amount of the compound of claim 1, or a salt thereof,thereby killing and/or preventing the growth of the protozoa, whereinthe protozoa is of a genus selected from the group consisting ofTrypanosoma, Leishmania, and Plasmodium.
 14. The method of claim 13,wherein the compound is according to claim 1, or a salt thereof.
 15. Themethod of claim 13, wherein the protozoa is of the genus Trypanosoma.16. The method of claim 13, wherein the protozoa is Trypanosoma brucei.17. The method of claim 16, wherein the Trypanosoma brucei is selectedfrom the group consisting of Trypanosoma brucei brucei, Trypanosomabrucei gambiense and Trypanosoma brucei rhodesiense.
 18. A method oftreating a disease in an animal, comprising: administering to the animala therapeutically effective amount of the compound of claim 1, or a saltthereof, thereby treating the disease, wherein the disease is associatedwith a protozoa of a genus selected from the group consisting ofTrypanosoma, Leishmania, and Plasmodium.
 19. The method of claim 18,wherein the compound is according to claim
 1. 20. The method of claim18, wherein the disease is sleeping sickness.
 21. The method of claim18, wherein the animal is a human.
 22. The compound of claim 2, or asalt thereof, wherein X is phenyl, substituted with at least one memberwhich is halosubstituted alkyl.
 23. The compound of claim 2, or a saltthereof, wherein X is phenyl, substituted with at least one member whichis trifluoromethyl.
 24. The compound of claim 1, or a salt thereof,having a structure according to the following formula:

wherein Y is halo-substituted C₁-C₆ alkyl.
 25. The compound of claim 24,or a salt thereof, wherein Y is C₁-C₆ alkyl, substituted with one, two,three, or four halogens.
 26. The compound of claim 24, or a saltthereof, wherein Y is C₁-C₆ alkyl, substituted with one, two, three, orfour fluorines.
 27. The compound of claim 24, or a salt thereof, whereinY is C₁-C₆ alkyl, substituted with one, two, three, or four chlorines.28. The compound of claim 24, or a salt thereof, wherein Y istrifluoromethyl.
 29. The compound of claim 24, or a salt thereof, whichisN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide.30. The compound of claim 24, or a salt thereof, which isN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)benzamide.31. The compound of claim 24, or a salt thereof, which isN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(trifluoromethyl)benzamide.32. The compound of claim 1, or a salt thereof, having a structureaccording to the following formula:

wherein Y⁵ is halosubstituted C₁-C₆ alkoxy.
 33. The compound of claim32, or a salt thereof, wherein Y⁵ is substituted with one or two orthree halogens.
 34. The compound of claim 32, or a salt thereof, whereinsaid Y⁵ is halosubstituted C₁-C₆ alkoxy, and said halosubstituted C₁-C₆alkoxy is fluoro-substituted C₁-C₆ alkoxy.
 35. The compound of claim 32,or a salt thereof, wherein said Y⁵ is halosubstituted C₁-C₆ alkoxy, andsaid halosubstituted C₁-C₆ alkoxy is trifluoro-substituted C₁-C₆ alkoxy.36. The compound of claim 1, or a salt thereof, which isN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethoxy)benzamide.37. The compound of claim 1, or a salt thereof, having a structureaccording to the following formula:

wherein each Y is an independently selected halo-substituted C₁-C₆alkyl.
 38. The compound of claim 37, or a salt thereof, wherein one Y isfluoro-substituted C₁-C₆ alkyl.
 39. The compound of claim 37, or a saltthereof, wherein one Y is trifluoro-substituted C₁-C₆ alkyl.
 40. Thecompound of claim 37, or a salt thereof, wherein each Y isfluoro-substituted C₁-C₆ alkyl.
 41. The compound of claim 37, or a saltthereof, wherein each Y is trifluoro-substituted C₁-C₆ alkyl.
 42. Thecompound of claim 1, or a salt thereof, which isN-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,4-bis-trifluoromethyl-benzamide.43. The compound of claim 1, or a salt thereof, which isN-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,5-bis-trifluoromethyl-benzamide.44. The compound of claim 1, or a salt thereof, which isN-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3,5-bis-trifluoromethyl-benzamide.45. The compound of claim 1, or a salt thereof, having a structureaccording to the following formula:

wherein each Y¹ is independently selected halogen, Y is halo-substitutedC₁-C₆ alkyl, R* is H or a negative charge.
 46. The compound of claim 5,or a salt thereof, wherein Y is fluoro-substituted C₁-C₆ alkyl.
 47. Thecompound of claim 45, or a salt thereof, wherein Y istrifluoro-substituted C₁-C₆ alkyl.
 48. The compound of claim 45, or asalt thereof, wherein Y is fluoro-substituted C₁-C₆ alkyl, and each Y¹is chloro.
 49. The compound of claim 45, or a salt thereof, wherein Y isfluoro-substituted C₁-C₆ alkyl, and each Y¹ is fluoro.
 50. The compoundof claim 45, or a salt thereof, wherein Y is fluoro-substituted C₁-C₆alkyl, a Y¹ is fluoro, and another Y¹ is chloro.
 51. The compound ofclaim 45, or a salt thereof, wherein Y is trifluoro-substituted C₁-C₆alkyl, and each Y¹ is chloro.
 52. The compound of claim 45, or a saltthereof, wherein Y is trifluoro-substituted C₁-C₆ alkyl, and each Y¹ isfluoro.
 53. The compound of claim 45, or a salt thereof, wherein Y istrifluoro-substituted C₁-C₆ alkyl, a Y¹ is fluoro, and another Y¹ ischloro.
 54. The compound of claim 45, or a salt thereof, having astructure which is


55. The compound of claim 45, or a salt thereof, having a structurewhich is


56. The compound of claim 45, or a salt thereof, having a structurewhich is


57. The compound of claim 1, or a salt thereof, wherein said compound is3-chloro-2-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-6-trifluoromethyl-benzamide.